Novel 1,3-dihydro-2h-indol-2-one derivatives and their use as ligands for v1b and v1a arginine-vasopressin receptors

ABSTRACT

The invention relates to compounds of formula:  
                 
 
     as well as the possible salts thereof with mineral or organic acids, and the solvates and/or hydrates thereof, which have affinity for and selectivity towards the V 1b  receptors or towards both the V 1b  and V 1a  receptors of arginine-vasopressin.  
     The invention also relates to the process for preparing them, to the intermediate compounds of formula (II) that are useful for preparing them, to pharmaceutical compositions containing them and to their use for the preparation of medicinal products.

[0001] The present invention relates to novel 1,3-dihydro-2H-indol-2-onederivatives, to a process for preparing them and to pharmaceuticalcompositions containing them.

[0002] The compounds according to the present invention have affinityfor and selectivity towards the V_(1b) receptors or towards both theV_(1b) and V_(1a) receptors of arginine-vasopressin (AVP).

[0003] AVP is a hormone which is known for its antidiuretic effect andits effect in regulating arterial pressure. It stimulates several typesof receptor: V₁ (V_(1a), V_(1b)), V₂. These receptors are located inparticular in the liver, the vessels (coronary, renal and cerebral), theplatelets, the kidneys, the uterus, the adrenal glands, the pancreas,the central nervous system and the pituitary gland. AVP thus exertscardiovascular, hepatic, pancreatic, antidiuretic andplatelet-aggregating effects and effects on the central and peripheralnervous system, and on the uterine sphere.

[0004] The location of the various receptors is described in: S. Jard etal., Vasopressin and oxytocin receptors: an overview, in Progress inEndocrinology. H. Imura and K. Shizurne ed., Experta Medica, Amsterdam,1988, 1183-1188, as well as in the following articles: J. Lab. Clin.Med., 1989, 114,(6), 617-632 and Pharmacol. Rev., 1991, 43(1), 73-108.

[0005] More particularly, the AVP V_(1a) receptors are located in manyperipheral organs and in the brain. They have been cloned in rats andman and they regulate most of the known effects of AVP: plateletaggregation; uterine contractions; the contraction of blood vessels;secretion of aldosterone, cortisol, CRF (corticotropin-releasing factor)and adrenocorticotrophic hormone (ACTH); hepatic glycogenolysis, cellproliferation and the main central effects of AVP (hypothermia, memory,etc.).

[0006] The V_(1b) receptors were initially identified in theadenohypophysis of various animal species (rats, pigs, bovines, sheep,etc.) including man (S. Jard et al., Mol. Pharmacol., 1986, 30, 171-177;Y. Arsenijevic et al., J. Endocrinol., 1994, 141, 383-391; J. Schwartzet al., Endocrinology, 1991, 129(2), 1107-1109; Y. De Keyser et al.,FEBS Letters, 1994, 356, 215-220) in which they stimulate the release ofadrenocorticotrophic hormone via AVP and potentiate the effects of CRFon the release of ACTH (G. E. Gillies et al., Nature, 1982, 299, 355).In the hypothalamus, the V_(1b) receptors also induce a direct releaseof CRF (Neuroendocrinology, 1994, 60, 503-508) and are, in these variousrespects, involved in stress situations.

[0007] These V_(1b) receptors have been cloned in rats, man and mice (Y.De Keyser, FEBS Letters, 1994, 356, 215-220; T. Sugimoto et al., J.Biol. Chem. 1994, 269(43), 27088-27092; M. Saito et al., Biochem.Biophys. Res. Commun., 1995, 212(3), 751-757; S. J. Lolait et al.,Neurobiology, 1996, 92, 6783-6787; M. A. Ventura et al., Journal ofMolecular Endocrinology, 1999, 22, 251-260) and various studies (in situhybridization, PCR [polymerase chain reaction], etc.) reveal theubiquitous presence of these receptors in various central tissues(brain, hypothalamus and adenohypophysis in particular) and peripheraltissues (kidney, pancreas, adrenals, heart, lungs, intestine, stomach,liver, mesentery, bladder, thymus, spleen, uterus, retina, thyroid,etc.) and in certain tumours (hypophyseal, pulmonary, etc.) suggesting abroad biological and/or pathological role for these receptors and apotential involvement in various diseases.

[0008] By way of example, in rats, studies have shown that AVP regulatesthe endocrine pancreas, via the V_(1b) receptors, by stimulating thesecretion of insulin and glucagon (B. Lee et al., Am. J. Physiol. 269(Endocrinol. Metab. 32): E1095-E1100, 1995) or the production ofcatecholamines in the medullo-adrenal which is the site of a localsynthesis of AVP (E. Grazzini et al., Endocrinology, 1996, 137(a),3906-3914). Thus, in the latter tissue, AVP is thought to have a crucialrole, via these receptors, in certain types of adrenal pheochromocytomaswhich secrete AVP and thereby induce a sustained production ofcatecholamines which are the cause of hypertension and which areresistant to angiotensin II-receptor antagonists and to conversionenzyme inhibitors. The adrenal cortex is also rich in V_(1a) receptorsinvolved in the production of glucocorticoids and mineralocorticoids(aldosterone and cortisol). Via these receptors, AVP (in the circulationor synthesized locally) can induce a production of aldosterone with anefficacy which is comparable to that of angiotensin II (G. Guillon etal., Endocrinology, 1995, 136(3), 1285-1295). Cortisol is a powerfulregulator of the production of ACTH, the stress hormone.

[0009] Recent studies have also shown that the adrenal glands arecapable of directly releasing CRF and/or ACTH via activation of theV_(1b) and/or V_(1a) receptors borne by the medullary cells (G.Mazzocchi et al., Peptides, 1997, 18(2), 191-195; E. Grazzini et al., J.Clin. Endocrinol. Metab., 1999, 84(6), 2195-2203).

[0010] The V_(1b) receptors are also considered as a label forACTH-secreting tumours such as certain pituitary tumours, certainbronchial carcinomas (SCLC [small lung cell cancers]), pancreatic,adrenal and thyroid carcinomas, inducing Cushing's, syndrome in certaincases (J. Bertherat et al., Eur. J. Endocrinol., 1996, 135, 173; G. A.Wittert et al., Lancet, 1990, 335, 991-994; G. Dickstein et al., J.Clin. Endocrinol. Metab., 1996, 81(8), 2934-2941). As regards the Viareceptors, they are a more specific label for small cell lung cancers(SCLC) (P. J. Woll et al., Biochem. Biophys. Res. Commun., 1989, 164(1),66-73). Thus, the compounds according to the present invention areobvious diagnostic tools and offer a novel therapeutic approach in theproliferation and detection of these tumours, even at an early stage(radiolabelling; SPECT [single photon emission computed tomography]; PETscan [positron emission tomography scanner]).

[0011] The abundant presence of the V_(1b) receptor messenger in thestomach and intestine suggests an involvement of AVP via this receptoron the release of gastrointestinal hormones such as cholecystokinin,gastrin or secretin (T. Sugimoto et al., Molecular cloning andfunctional expression of V_(1b) receptor gene, in Neurohypophysis:Recent Progress of Vasopressin and Oxytocin Research; T. Saito, K.Kurokawa and S. Yoshida ed., Elvesier Science, 1995, 409-413).

[0012] 1,3-Dihydro-2H-indol-2-one derivatives have been described incertain patent applications as arginine-vasopressin receptor ligandsand/or oxytocin receptor ligands: mention may be made of patentapplications WO 93/15051, EP-A-0 636 608. EP-A-0 636 609, WO 95/18105,WO 97/15556 and WO 98/25901.

[0013] No non-peptide compound with affinity for and selectivity towardsthe V_(1b) receptors or simultaneously for and towards both the V_(1b)and V_(1a) receptors of arginine-vasopressin is known to date.

[0014] Novel 1,3-dihydro-2H-indol-2-one derivatives have now been foundwhich have affinity for and selectivity towards the V_(1b) receptors orfor and towards both the V_(1b) and V_(1a) receptors ofarginine-vasopressin.

[0015] These compounds may be used for the preparation of medicinalproducts that are useful in the treatment or prevention of any pathologyin which arginine-vasopressin and/or the V_(1b) receptors or both theV_(1b) receptors and the V_(1a) receptors are involved, in particular inthe treatment or prevention of complaints of the cardiovascular system,for example hypertension; of the central nervous system, for examplestress, anxiety, depression, compulsive obsessive disorder and panicattacks; of the renal system; of the gastric system as well as in thetreatment of small cell lung cancers; of obesity; of type II diabetes;of insulin resistance; of hypertriglyceridemia; of atherosclerosis; ofCushing's syndrome; of any pathology following stress and chronic stressstates.

[0016] Thus, according to one of its aspects, one subject of the presentinvention is compounds of formula:

[0017] in which:

[0018] R₁ represents a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; atrifluoromethyl radical; a trifluoromethoxy radical;

[0019] R₂ represents a hydrogen atom; a halogen atom; a (C₁-C₄)alkyl; a(C₁-C₄)alkoxy; a trifluoromethyl radical;

[0020] or R₂ is in position -6- of the indol-2-one ring and R₁ and R₂together represent a divalent trimethylene radical;

[0021] R₃ represents a halogen atom; a hydroxyl; a (C₁-C₂)alkyl; a(C₁-C₂)alkoxy; a trifluoromethoxy radical;

[0022] R₄ represents a hydrogen atom; a halogen atom; a (C₁-C₂)alkyl; a(C₁-C₂)alkoxy;

[0023] or R₄ is in position -3- of the phenyl and R₃ and R₄ togetherrepresent a methylenedioxy radical;

[0024] R₅ represents an ethylamino group; a dimethylamino group; anazetidin-1-yl radical; a (C₁-C₂)alkoxy;

[0025] R₆ represents a hydrogen atom; a (C₁-C₄)alkyl; a group—(CH₂)n-CO—R₉; a group —CO—(CH₂)n-NR₁₁;

[0026] R₇ represents a (C₁-C₄)alkoxy;

[0027] R₈ represents a (C₁-C₄)alkoxy;

[0028] R₉ represents a hydroxyl; a (C₁-C₄)alkoxy; a group —NR₁₂R₁₃;

[0029] R₁₀ and R₁₁ each independently represent a (C₁-C₄) alkyl;

[0030] or R₁₀ and R₁₁, together with the nitrogen atom to which they areattached, constitute a heterocyclic radical chosen from: azetidin-1-yl,pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl orthiomorpholin-4-yl;

[0031] R₁₂ represents a hydrogen or a (C₁-C₄)alkyl;

[0032] R₁₃ represents a (C₁-C₄)alkyl; a —C(CH₃)₂CH₂OH group; a —C(CH₃)(CH₂OH)₂ group; a —C(CH₂OH)₃ group;

[0033] or R₁₂ and R₁₃, together with the nitrogen atom to which they areattached, constitute a heterocyclic radical chosen from: azetidin-1-yl,pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl orthiomorpholin-4-yl;

[0034] n is 1 or 2;

[0035] as well as the solvates and/or hydrates thereof and the possiblesalts thereof with mineral or organic acids.

[0036] The term “halogen atom” means a chlorine, bromine, fluorine oriodine atom.

[0037] The terms “alkyl” and “alkoxy”, respectively, mean a linear orbranched alkyl radical or alkoxy radical, respectively.

[0038] The compounds of formula (I) comprise at least 3 asymmetriccarbon atoms, the carbon atom bearing the substituent COR₅ has the (S)configuration, and the carbon atom bearing the substituent OR₆ haseither the (R) configuration or the (S) configuration. The opticallypure isomers of the compounds of formula (I) and the mixtures thereof inall proportions form part of the invention.

[0039] The salts are generally prepared with pharmaceutically acceptableacids, but the salts of other acids which are useful for purifying orisolating the compounds of formula (I) also form part of the invention.The pharmaceutically acceptable salts of the compounds of formula (I)are, for example, the hydrochloride, hydrobromide, sulphate, hydrogensulphate, dihydrogen phosphate, methanesulphonate, benzenesulphonate,naphthalenesulphonate, paratoluenesulphonate, maleate, fumarate,succinate, citrate, acetate, gluconate or oxalate.

[0040] According to the present invention, the compounds of formula (I)that are preferred are those in which:

[0041] R₁ represents a halogen atom; a (C₁-C₄)alkyl; a trifluoromethylradical; a trifluoromethoxy radical;

[0042] R₂ represents a hydrogen atom; a halogen atom; a (C₁-C₄)alkyl; a(C₁-C₄)alkoxy; a trifluoromethyl radical;

[0043] or R₂ is in position -6- of the indol-2-one ring and R₁ and R₂together represent a divalent trimethylene radical;

[0044] R₃ represents a halogen atom; a hydroxyl; a (C₁-C₂) alkoxy;

[0045] R₄ represents a hydrogen atom; a halogen atom; a (C₁-C₂)alkyl; a(C₁-C₂)alkoxy;

[0046] or R₄ is in position -3- of the phenyl and R₃ and R₄ togetherrepresent a methylenedioxy radical;

[0047] R₅ represents an ethylamino group; a dimethylamino group; anazetidin-1-yl group; a (C₁-C₂)alkoxy;

[0048] R₆ represents a hydrogen atom; a (C₁-C₄)alkyl;

[0049] R₇ represents a (C₁-C₄)alkoxy;

[0050] R₈ represents a (C₁-C₄)alkoxy;

[0051] as well as the solvates and/or hydrates thereof and the possiblesalts thereof with mineral or organic acids.

[0052] According to the present invention, the compounds of formula (I)in which R₁ represents a chlorine atom, a methyl radical or atrifluoromethoxy radical are preferred.

[0053] According to the present invention, the compounds of formula (I)in which R₂ represents a hydrogen atom or is in position -6- of theindol-2-one and represents a chlorine atom, a methyl radical, a methoxyradical or a trifluoromethyl radical are preferred.

[0054] According to the present invention, the compounds of formula (I)in which R₃ represents a chlorine atom, a fluorine atom, a methoxyradical, an ethoxy radical or a trifluoromethoxy radical are preferred.

[0055] According to the present invention, the compounds of formula (I)in which R₄ represents a hydrogen atom or is in position -3- or -4- ofthe phenyl and represents a fluorine atom or a methoxy radical; or R₄ isin position -3- of the phenyl and, together with R₃, represent amethylenedioxy radical, are preferred.

[0056] According to the present invention, the compounds of formula (I)in which R₅ represents a dimethylamino group, an azetidin-1-yl radicalor a methoxy radical are preferred.

[0057] According to the present invention, the compounds of formula (I)in which R₆ represents a halogen atom, a methyl radical, an ethylradical, a tert-butoxycarbonylmethyl radical, a carboxymethyl radical, a[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]carbonylmethylradical, a (1-piperazinyl)carbonylmethyl radical, a(4-morpholinyl)carbonylmethyl radical or a 3-(4-morpholinyl)propanoylradical are preferred.

[0058] According to the present invention, the compounds of formula (I)in which R₇ is in position -2- or -3- of the phenyl and represents amethoxy radical are preferred.

[0059] According to the present invention, the compounds of formula (I)in which R₈ represents a methoxy radical are preferred.

[0060] According to the present invention, the compounds of formula (I)in the form of optically pure isomers are preferred.

[0061] Particularly preferred are the optically pure isomers of thecompounds of formula:

[0062] in which R₁, R₂, R₃, R₄, R₅, R₆, R₇ and R₈ are as defined for acompound of formula (I), the carbon atom bearing substituent OR₆ has the(R) configuration and the carbon atom in position 3 of the indol-2-onehas either the (R) configuration or the (S) configuration.

[0063] The laevorotatory isomer of the compounds of formula (Ia) is moreparticularly preferred.

[0064] Most particularly preferred are the compounds of formula (Ia),laevorotatory isomer, in which:

[0065] R₁ represents a chlorine atom, a methyl radical or atrifluoromethoxy radical;

[0066] R₂ represents a hydrogen atom or is in position -6- of theindol-2-one and represents a chlorine atom, a methyl radical, a methoxyradical or a trifluoromethyl radical;

[0067] R₃ represents a chlorine atom, a fluorine atom, a methoxy radicalor an ethoxy radical;

[0068] R₄ represents a hydrogen atom or is in position -3- or -4- of thephenyl and represents a fluorine atom or a methoxy radical;

[0069] or R₄ is in position -3- of the phenyl and, together with R₃,represent a methylenedioxy radical;

[0070] R₅ represents a dimethylamino radical or a methoxy radical;

[0071] R₆ represents a hydrogen atom; a methyl radical; an ethylradical; a Lert-butyloxycarbonylmethyl radical; a carboxymethyl radical;a [[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]carbonylmethylradical; a (1-piperazinyl)carbonylmethyl radical; a(4-morpholinyl)carbonylmethyl radical; a 3-(4-morpholinyl)propanoylradical;

[0072] R₇ is in position -2- of the phenyl and represents a methoxyradical;

[0073] R₈ represents a methoxy radical;

[0074] as well as the salts thereof with mineral or organic acids, andthe solvates and/or hydrates thereof.

[0075] The following compounds:

[0076](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0077](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0078](2S,4R)-1-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide,laevorotatory isomer;

[0079](2S,4R)-1-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0080](2S,4R)-1-[5-Chloro-1-[(3,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer;

[0081] Methyl(2S,4R)-1-[5-chloro-3-(2-methoxyphenyl)-1-[(3,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-2-pyrrolidine-carboxylate,laevorotatory isomer;

[0082](2S,4R)-1-[5-Methyl-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0083](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(azetidin-1-ylcarbonyl)-4-hydroxypyrrolidinecarboxamide,laevorotatory isomer;

[0084](2S,4R)-1-[5-Trifluoromethoxy-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0085](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0086](2S,4R)-1-[3-(2-Chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0087](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0088](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0089](2S,4R)-1-[6-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0090](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-ethoxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0091](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0092](2S,4R)-1-[5,6-Dichloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide,laevorotatory isomer;

[0093]Methyl(2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-2-pyrrolidinecarboxylate,laevorotatory isomer;

[0094]Methyl(2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-2-pyrrolidinecarboxylate,laevorotatory isomer;

[0095](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide,laevorotatory isomer;

[0096](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2,3-difluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0097](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2,4-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0098](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(1,3-benzodioxol-4-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0099](2S,4R)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0100] tert-Butyl2-[[(3R,5S)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]acetate,laevorotatory isomer;

[0101]2-[[(3R,5S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]aceticacid, laevorotatory isomer;

[0102](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-[2-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-2-oxoethoxy]-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0103](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-4-[2-oxo-2-(1-piperazinyl)ethoxy]-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0104](2S,4R)-1-[[(2,4-Dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-4-[2-oxo-2-(4-morpholinyl)ethoxy]-2-pyrrolidinecarboxamide,laevorotatory isomer;

[0105] (3R,5S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl3-(4-morpholinyl)propanoate, laevorotatory isomer;

[0106] as well as the possible salts thereof with mineral or organicacids, and the solvates and/or hydrates thereof are more particularlypreferred.

[0107] According to another of its aspects, a subject of the presentinvention is a process for preparing compounds of formula (I), possiblesalts thereof with mineral or organic acids, and solvates and/orhydrates thereof, characterized in that:

[0108] a compound of formula:

[0109] in which R₁, R₂, R₃, R₄, R₅ and R₆ are as defined for a compoundof formula (I), is reacted, in the presence of a base, with a halide offormula:

[0110] in which R₇ and R₈ are as defined for a compound of formula (I)and Hal represents a halogen atom.

[0111] The compound of formula (I) is optionally converted into a saltthereof with mineral or organic acids.

[0112] The reaction is carried out in the presence of a strong base, forinstance a metal hydride such as sodium hydride or an alkali metalalkoxide such as potassium tert-butoxide, in an anhydrous solvent suchas N,N-dimethylformamide or tetrahydrofuran and at a temperature ofbetween −70° C. and +60° C. The reaction is preferably carried out usinga compound of formula (III) in which Hal=Cl.

[0113] A compound of formula (I) in which R₆ represents a (C₁-C₄)alkylmay also be prepared by reacting a compound of formula (I) in which R₆represents hydrogen with a (C₁-C₄)alkyl halide, in the presence of abase such as a metal hydride, in an inert solvent such asN,N-dimethylformamide or tetrahydrofuran according to the conventionalmethods.

[0114] A compound of formula (I) in which R₆ represents a group—(CH₂)n-CO—R₉ in which R₉ represents a hydroxyl is preferably preparedby hydrolysing a compound of formula (I) in which R₆ represents a group—(CH₂)n-CO—R₉ in which R₉ represents a tert-butyloxy, in acidic medium,using a strong acid such as trifluoroacetic acid or hydrochloric acid ina solvent such as dichloromethane or dioxane and at a temperature ofbetween 0° C. and room temperature.

[0115] A compound of formula (I) in which R₆ represents a group—(CH₂)n-CO—R₉ in which R₉ represents a group —NR₁₂R₁₃ is preferablyprepared by reacting a compound of formula (I) in which R₉ represents ahydroxyl with an amine of formula H—NR₁₂R₁₃ according to theconventional methods of peptide coupling.

[0116] The compounds of formula (I) thus obtained may be subsequentlyseparated from the reaction medium and purified according to theconventional methods, for example by crystallization or chromatography.

[0117] The compounds of formula (I) thus obtained are isolated in freebase or salt form, according to the conventional techniques.

[0118] When the compounds of formula (I) are obtained in free base form,the salification is carried out by treatment with the selected acid inan organic solvent. By treating the free base, dissolved, for example,in an ether such as diethyl ether or in an alcohol such as 2-propanol orin acetone or in dichloromethane, or in ethyl acetate or inacetonitrile, with a solution of the selected acid in one of theabovementioned solvents, the corresponding salt is obtained, which isisolated according to the conventional techniques.

[0119] Thus, the hydrochloride, hydrobromide, sulphate,trifluoroacetate, hydrogen sulphate, dihydrogen phosphate,methanesulphonate, oxalate, maleate, succinate, fumarate,2-naphthalenesulphonate, benzenesulphonate, para-toluenesulphonate,gluconate, citrate or acetate is prepared, for example.

[0120] At the end of the reaction, the compounds of formula (I) may beisolated in the form of a salt thereof, for example the hydrochloride oroxalate; in this case, if necessary, the free base may be prepared byneutralizing the said salt with a mineral or organic base, such assodium hydroxide or triethylamine or with an alkali metal carbonate orbicarbonate, such as sodium or potassium carbonate or bicarbonate.

[0121] The compounds of formula (II) are prepared by reacting a3-halo-1,3-dihydro-2H-indol-2-one compound of formula:

[0122] in which R₁, R₂, R₃ and R₄ are as defined for a compound offormula (I) and Hal represents a halogen atom, preferably chlorine orbromine, with a compound of formula:

[0123] in which R₅ and R₆ are as defined for a compound of formula (I).The reaction is carried out in the presence of a base such asdiisopropylethylamine or triethylamine, in an inert solvent such asdichloromethane or tetrahydrofuran or a mixture of these solvents and ata temperature of between room temperature and the reflux temperature ofthe solvent.

[0124] The compounds of formula (III) are known or prepared by knownmethods such as those disclosed in EP-B-0 469 984 and WO 95/18105. Forexample, the compounds of formula (III) may be prepared by halogenatingthe corresponding benzenesulphonic acids or salts thereof, for examplethe sodium or potassium salts thereof. The reaction is carried out inthe presence of a halogenating agent such as phosphorus oxychloride,thionyl chloride, phosphorus trichloride, phosphorus tribromide orphosphorus pentachloride, without solvent or in an inert solvent such asa halogenated hydrocarbon or N,N-dimethylformamide and at a temperatureof between −10° C. and 200° C.

[0125] 2,4-Dimethoxybenzenesulphonyl chloride is prepared according toJ. Am. Chem. Soc., 1952, 74, 2008. 3,4-Dimethoxybenzenesulphonylchloride is commercially available or is prepared according to J. Med.Chem., 1977, 20(10), 1235-1239.

[0126] The compounds of formula (IV) are known and are preparedaccording to known methods such as those disclosed in WO 95/18105.

[0127] For example, a compound of formula:

[0128] in which R₁, R₂, R₃ and R₄ are as defined for a compound offormula (I), is converted into a compound of formula (IV) in whichHal=Cl by the action of thionyl chloride in the presence of a base suchas pyridine, in an inert solvent such as dichloromethane and at atemperature of between 0° C. and room temperature.

[0129] According to another example for preparing the compounds offormula (IV), a compound of formula:

[0130] in which R₁, R₂, R₃ and R₄ are as defined for a compound offormula (I), is converted into a compound of formula (IV) by means of ahalogenating agent such as bromine, according to the process disclosedin Farm. Zh.(Kiev), 1976, 5, 30-33.

[0131] The compounds of formula (VI) are known and are preparedaccording to known methods such as those disclosed in WO 95/18105.

[0132] For example, a compound of formula (VI) is prepared by reacting a1H-indole-2,3-dione derivative of formula:

[0133] in which R₁ and R₂ are as defined for a compound of formula (I),with an organomagnesium derivative of formula:

[0134] in which R₃ and R₄ are as defined for a compound of formula (I)and Hal represents a halogen atom, preferably bromine or iodine, in aninert solvent such as tetrahydrofuran or diethyl ether.

[0135] It is also possible to prepare a compound of formula (VI) inwhich R₃ is as defined for a compound of formula (I) and R₄, which isother than hydrogen, is in position -3- or -6- of the phenyl, byreacting a compound of formula:

[0136] in which R₃ is as defined for a compound of formula (I) and R₄ isin position -2- or -5- of the phenyl, with a lithium derivative such asn-butyllithium, and the lithiated intermediate thus obtained is thenreacted with a compound of formula (VIII). The reaction is carried outin a solvent such as diethyl ether, tetrahydrofuran or hexane or amixture of these solvents, at a temperature of between −70° C. and roomtemperature.

[0137] The 1H-indole-2,3-dione derivatives (VIII) are commerciallyavailable or are prepared according to the methods disclosed inTetrahedron Letters, 1998, 39, 7679-7682; Tetrahedron Letters, 1994, 35,7303-7306; J. Org. Chem., 1977, 42(8), 1344-1348; J. Org. Chem., 1952,17, 149-156; J. Am. Chem. Soc., 1946, 68, 2697-2703; Organic Syntheses,1925, V, 71-74 and Advances in Heterocyclic Chemistry, A. R. Katritzkyand A. J. Boulton, Academic Press, New York, 1975, 18, 2-58.

[0138] The organomagnesium derivatives (1×) are prepared according tothe conventional methods that are well known to those skilled in theart.

[0139] The compounds of formula (XVII) are known or prepared accordingto known methods.

[0140] A compound of formula (VI) may also be prepared by air-oxidationof a compound of formula (VII) in the presence of a base such as sodiumhydride and in the presence of dimethyl disulphide.

[0141] In particular, the compounds of formula (VI) in whichR₃=(C₁-C₂)alkoxy and R₄=H, or R₃=R₄=(C₁-C₂)alkoxy with R₄ in position -3or -6 of the phenyl, R₂ is other than a halogen atom and R₁ is asdefined for a compound of formula (I), may be prepared by following theprocess described in Scheme 1.

[0142] In step a1 of Scheme 1, a compound of formula (X) is firstreacted with a lithium derivative such as n-butyllithium, in the absenceor presence of a base such as N,N,N′,N′-tetramethylenediamine, and thelithiated intermediate thus obtained is then reacted with diethyloxalate to give the compound of formula (XI). The reaction is carriedout in an inert solvent such as diethyl ether, tetrahydrofuran or hexaneor a mixture of these solvents and at a temperature of between −70° C.and room temperature.

[0143] In step b1, a compound of formula (XII) is first reacted with twoequivalents of a lithium derivative such as tert-butyllithium, and thelithiated intermediate thus obtained is then reacted with the compoundof formula (XI) to give the expected compound of formula (VI). Thereaction is carried out in an inert solvent such as diethyl ether,tetrahydrofuran or pentane or a mixture of these solvents and at atemperature of between −70° C. and room temperature.

[0144] The compounds of formula (X) are commercially available orsynthesized conventionally.

[0145] The compounds of formula (XII) are prepared by reacting thecorresponding aniline derivatives with di-tert-butyl dicarbonateaccording to the conventional methods.

[0146] The compounds of formula (VII) are known and are preparedaccording to known methods such as those disclosed in WO 95/18105 or inJ. Org. Chem., 1968, 33, 1640-1643.

[0147] The compounds of formula (V) in which R₅ represents a(C₁-C₂)alkoxy and R₆<H are commercially available.

[0148] The compounds of formula (V) in which R₅ represents a(C₁-C₂)alkoxy and R₆=(C₁-C₄)alkyl are known or are prepared according toknown methods such as those disclosed in J. Med. Chem., 1988, 31,875-885 starting with (2S,4R)- or(2S,4S)-4-hydroxy-pyrrolidine-2-carboxylic acid protected on thenitrogen atom of the pyrrolidine.

[0149] The compounds of formula (V) in which R₅ is an ethylamino ordimethylamino group or an azetidin-1-yl radical and R₆=H or (C₁-C₄)alkylare prepared according to Scheme 2 below in which Pr represents anN-protecting group, in particular benzyloxycarbonyl ortert-butoxycarbonyl.

[0150] In step a2 of Scheme 2, the nitrogen atom of the 4(R)- or4(S)-hydroxy-(S)-proline is protected according to the conventionalmethods to obtain a compound of formula (XIII).

[0151] The acid (XIII) is reacted in step b2 with ethylamine,dimethylamine or azetidine according to the conventional methods ofpeptide coupling to give the compound (XIV), which is deprotected,according to the known methods, to give a compound of formula (V) inwhich R₆=H.

[0152] In step d2, the compound (XIV) may be reacted with a (C₁-C₄)alkylhalide, in the presence of a base such as a metal hydride or an alkalimetal carbonate or alkaline-earth metal carbonate such as K₂CO₃ orCs₂CO₃, in an inert solvent such as tetrahydrofuran orN,N-dimethylformamide and at a temperature of between 0° C. and thereflux temperature of the solvent, to give a compound (XV).

[0153] It is also possible to carry out the reaction of a compound (XIV)with a (C₁-C₄)alkyl halide under conditions of phase-transfer catalysis,in the presence of a base such as an alkali metal hydroxide, for examplesodium hydroxide, and of a phase-transfer catalyst such as a substitutedquaternary ammonium salt, for example tetrabutylammonium hydrogensulphate, in an inert solvent such as dichloromethane or benzene as amixture with water.

[0154] Deprotection of the N-protecting group of compound (XV) gives, instep e2, the compounds of formula (V) in which R₆=(C₁-C₄)alkyl.

[0155] Alternatively, in step f2, the hydroxyl of compound (XIII) isalkylated by reaction with a (C₁-C₄)alkyl halide under the conditions ofstep d2, and the acid (XVI) thus obtained is reacted in step g2 withethylamine, dimethylamine or azetidine according to the conventionalmethods of peptide coupling to give compound (XV).

[0156] (2S,4R)- and (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid arecommercially available.

[0157] The compounds of formula (V) in which R₅ represents an ethylaminogroup, a dimethylamino group, an azetidin-1-yl radical or a(C₁-C₂)alkoxy and R₆=—(CH₂)n-CO—R₉ in which n is 1 or 2 and R₉represents a (C₁-C₄)alkoxy are prepared according to Scheme 3 below inwhich Pr represents an N-protecting group, in particularbenzyloxycarbonyl or tert-butoxycarbonyl.

[0158] In step a3 of Scheme 3, a compound of formula (XVIII), preparedas described above, is reacted with a compound of formulaHal-(CH₂)n-COR₉ in which Hal represents a halogen atom, preferablychlorine or bromine, n is 1 or 2 and R₉ represents a (C₁-C₄)alkoxy. Thereaction is carried out under the conditions described above in step d2of Scheme 2, to give a compound (XIX).

[0159] Deprotection of the N-protecting group of compound (XIX) gives,in step b3, the expected compounds (V).

[0160] The compounds of formula (V) in which R₅ is as defined for acompound of formula (I) and R₆=—(CH₂)n-CO—R₉ in which n is 1 or 2 and R₉represents a hydroxyl are prepared by acidic hydrolysis of a compound offormula (XIX) in which R₉ represents a tert-butoxy and Pr represents abenzyloxycarbonyl. The reaction is carried out using a strong acid suchas trifluoroacetic acid or hydrochloric acid in a solvent such asdichloromethane or dioxane and at a temperature of between 0° C. androom temperature. Deprotection of the N-protecting group according tothe conventional methods gives the expected compounds (V).

[0161] The compounds of formula (V) in which R₅ is as defined for acompound of formula (I) and R₆=—(CH₂)n-CO—R₉ in which n is 1 or 2 and R₉represents a group —NR₁₂R₁₃ are prepared by reacting a correspondingcompound in which R₉ represents a hydroxyl and protected on the nitrogenatom of the pyrrolidine, with an amine HNR₁₂R₁₃ according to theconventional methods of peptide coupling.

[0162] Deprotection of the N-protecting group according to theconventional methods gives the expected compounds (V).

[0163] The compounds of formula (V) in which R₅ represents an ethylaminogroup, a dimethylamino group, an azetidin-1-yl radical or a(C₁-C₂)alkoxy and R₆=—CO—(CH₂)n-NR₁₀R₁₁ in which n is 1 or 2 and R₁₀ andR₁₁ are as defined for a compound of formula (I) are prepared accordingto Scheme 4 below in which Pr represents an N-protecting group, inparticular benzyloxycarbonyl or tert-butoxycarbonyl.

[0164] In step a4 of Scheme 4, a compound of formula (XVIII) is reactedwith a compound of formula Hal-CO—(CH₂)n-Hal′ in which Hal and Hal′ eachindependently represent a halogen atom, preferably chlorine or bromine,and n is 1 or 2. The reaction is carried out in the presence of a basesuch as triethylamine or diisopropylethylamine, in a solvent such asdichloromethane or tetrahydrofuran and at a temperature of between 0° C.and the reflux temperature of the solvent.

[0165] In step b4, the reaction of the compound of the formula (XX) thusobtained with a compound of formula HNR₁₀R₁₁ gives a compound of formula(XXI). The reaction is carried out in the presence of a base such astriethylamine or N,N-diisopropylethylamine, or using an excess of thecompound HNR₁₀R₁₁, in a solvent such as dichloromethane ortetrahydrofuran and at a temperature of between 0° C. and the refluxtemperature of the solvent.

[0166] Deprotection of the N-protecting group of compound (XXI) gives,in step c4, the expected compound of formula (V).

[0167] In particular, a compound of formula (V) in whichR₆=—CO—(CH₂)n-NR₁₀R₁₁ in which n is 2 can also be prepared according toScheme 5 below in which Pr represents an N-protecting group, inparticular benzyloxycarbonyl or tert-butoxycarbonyl.

[0168] In step a5 of Scheme 5, a compound of formula (XVIII) is reactedwith acryloyl chloride, under the conditions described above in step a4of Scheme 4, to give the compound of formula (XXII).

[0169] In step b5, the reaction of compound (XXII) with a compound offormula HNR₁₀R₁₁ gives a compound of formula (XXIII). The reaction iscarried out in the presence of ferric chloride, in a solvent such asdichloromethane and at a temperature of between room temperature and thereflux temperature of the solvent.

[0170] Deprotection of the N-protecting group of compound (XXIII) gives,in step c5, the expected compound of formula (V).

[0171] When it is desired to prepare an optically pure compound offormula (I), an optically pure compound of formula (II) is preferablyreacted with a compound of formula (III) according to the process of theinvention.

[0172] The optically pure compounds of formula (II) are prepared byreacting the racemic compound of formula (IV) with an optically purecompound of formula (V), followed by separation of the mixture ofdiastereoisomers according to the conventional methods, for example bycrystallization or chromatography.

[0173] Alternatively, the mixture of diastereoisomers of the compound offormula (II) can be reacted with the compound of formula (III) and themixture of diastereoisomers of the compound of formula (I) thus obtainedcan be separated.

[0174] During any of the steps for preparing the compounds of formula(I) or the intermediate compounds of formula (II), (IV), (V) or (VI), itmay be necessary and/or desirable to protect the reactive or sensitivefunctional groups, such as the amine, hydroxyl or carboxyl groups,present on any of the molecules concerned. This protection may becarried out using conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, J. F. W. McOmie,published by Plenum Press, 1973, in Protective Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, published by John Wiley &Sons, 1991 or in Protecting Groups, Kocienski P. J., 1994, Georg ThiemeVerlag. The removal of the protecting groups may be carried out in asuitable subsequent step using the methods known to those skilled in theart which do not affect the rest of the molecule concerned.

[0175] The N-protecting groups optionally used are the conventionalN-protecting groups that are well known to those skilled in the art,such as, for example, the tert-butoxycarbonyl, fluorenylmethoxycarbonyl,benzyl, benzhydrylidene or benzyloxycarbonyl group.

[0176] The compounds of formula (II) are novel and form part of theinvention.

[0177] Thus, according to another of its aspects, a subject of theinvention is compounds of formula:

[0178] in which:

[0179] R₁ represents a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; atrifluoromethyl radical; a trifluoromethoxy radical;

[0180] R₂ represents a hydrogen atom; a halogen atom; a (C₁-C₄)alkyl; a(C₁-C₄)alkoxy; a trifluoromethyl radical;

[0181] or R₂ is in position -6- of the indol-2-one ring and R₁ and R₂together represent a divalent trimethylene radical;

[0182] R₃ represents a halogen atom; a hydroxyl; a (C₁-C₂)alkyl; a(C₁-C₂)alkoxy; a trifluoromethoxy radical;

[0183] R₄ represents a hydrogen atom; a halogen atom; a (C₁-C₂)alkyl; a(C₁-C₂)alkoxy;

[0184] or R₄ is in position -3- of the phenyl and R₃ and R₄ togetherrepresent a methylenedioxy radical;

[0185] R₅ represents an ethylamino group; a dimethylamino group; anazetidin-1-yl radical; a (C₁-C₂)alkoxy;

[0186] R₆ represents a hydrogen atom; a (C₁-C₄)alkyl; a group—(CH₂)n-CO—R₉; a group —CO—(CH₂)n-NR₁OR₁₁;

[0187] R₉ represents a hydroxyl; a (C₁-C₄)alkoxy; a group —NR₁₂R₁₃;

[0188] R₁₀ and R₁₁ each independently represent a (C₁-C₄)alkyl;

[0189] or R₁₀ and R₁₁, together with the nitrogen atom to which they areattached, constitute a heterocyclic radical chosen from: azetidin-1-yl,pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl orthiomorpholin-4-yl;

[0190] R₁₂ represents a hydrogen or a (C₁-C₄)alkyl;

[0191] R₁₃ represents a (C₁-C₄)alkyl; a —C(CH₃)₂CH₂OH group; a —C(CH₃)(CH₂OH)₂ group; a —C(CH₂OH)₃ group;

[0192] or R₁₂ or R₁₃, together with the nitrogen atom to which they areattached, constitute a heterocyclic radical chosen from: azetidin-1-yl,pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl orthiomorpholin-4-yl;

[0193] n is 1 or 2;

[0194] as well as the salts thereof with mineral or organic acids, inthe form of optically pure isomers or in the form of a mixture ofdiastereoisomers.

[0195] The salts of compounds of formula (II) comprise those withmineral or organic acids which allow a suitable separation orcrystallization of the compounds of formula (II) such as thehydrochloride, hydrobromide, oxalate, maleate, succinate, fumarate,citrate or acetate.

[0196] The compounds of formula (I) above also comprise those in whichone or more hydrogen or carbon atoms have been replaced with theirradioactive isotope, for example tritium or carbon-14. Such labelledcompounds are useful in metabolic or pharmacokinetic research studies,in biochemical assays as receptor ligands.

[0197] The compounds according to the invention have undergonebiochemical studies.

[0198] The affinity of the compounds of formula (I) according to theinvention for the arginine-vasopressin V_(1b) receptors was determinedin vitro using the method disclosed by Y. De Keyser et al., FebsLetters, 1994, 356, 215-220. This method consists in studying in vitrothe displacement of tritiated arginine-vasopressin ([³H]-AVP) from theV_(1b) receptors present on rat or human adenohypophyseal or cellmembrane preparations bearing the V_(1b) receptors. The concentrationsof the compounds according to the invention which inhibit 50% (IC₅₀) ofthe binding of the tritiated arginine-vasopressin are low and range from10⁻⁶ to 10⁻⁹ M, more particularly from 10⁻⁷ to 10⁻⁹ M.

[0199] The affinity of the compounds of formula (I) according to theinvention for the arginine-vasopressin V_(1a) receptors was determinedin vitro using the method disclosed by M. Thibonnier et al., J. Biol.Chem., 1994, 269, 3304-3310. This method consists in studying in vitrothe displacement of tritiated arginine-vasopressin ([³H]-AVP) from theV_(1a) receptors present on rat or human cell or membrane preparationsbearing the V_(1a) receptors. Among the compounds of formula (I), somealso have affinity for the arginine-vasopressin V_(1a) receptors withIC₅₀ values which range from 10-6 to 10⁻⁹ M, more particularly from 10⁻⁷to 10⁻⁸ M.

[0200] The affinity of the compounds of formula (I) according to theinvention for the vasopressin V₂ receptors was also studied (methoddisclosed by M. Birnbaumer et al., Nature (Lond.), 1992, 357, 333-335).The compounds studied have little or no affinity for the V₂ receptors.

[0201] Compounds of the present invention are especially activeprinciples of pharmaceutical compositions, the toxicity of which iscompatible with their use as medicinal products.

[0202] According to another of its aspects, the present inventionrelates to the use of the compounds of formula (I), or apharmaceutically acceptable salt, solvate and/or hydrate thereof, forthe preparation of medicinal products intended for treating anypathology in which arginine-vasopressin and/or its V_(1b) receptors orboth its V_(1b) receptors and its Via receptors are involved.

[0203] According to another of its aspects, the present inventionrelates to the use of compounds of formula (I), or a pharmaceuticallyacceptable salt, solvate and/or hydrate thereof, for the preparation ofmedicinal products intended for treating pathologies of thecardiovascular system, of the central nervous system, of the renalsystem or of the gastric system, as well as small cell lung cancers,obesity, type II diabetes, insulin resistance, hypertriglyceridaemia, ofatherosclerosis, Cushing's syndrome, all stress-related pathologies andchronic stress states.

[0204] Thus, the compounds according to the invention may be used, inman or animals, in the treatment or prevention of variousvasopressin-dependent complaints such as cardiovascular complaints, forinstance hypertension, pulmonary hypertension, cardiac insufficiency,myocardial infarction or coronary vasospasm, in particular in smokers,Raynaud's disease, unstable angina and PTCA (percutaneous transluminalcoronary angioplasty), cardiac ischaemia, haemostasis disorders;complaints of the central nervous system such as migraine, cerebralvasospasm, cerebral haemorrhage, cerebral oedema, depression, anxiety,stress, obsessive-compulsive disorder, panic attacks, psychotic statesand memory disorders, for example; complaints of the renal system suchas renal vasospasm, renal cortex necrosis, nephrogenic diabetesinsipidus; complaints of the gastric system such as gastric vasospasm,cirrhosis of the liver, ulcers, vomiting pathology, for example nauseaincluding nausea caused by chemotherapy and travel sickness; diabeticnephropathy. The compounds according to the invention may also be usedin the treatment of disorders of sexual behaviour; in women, thecompounds according to the invention may be used to treat dysmenorrhoeaor premature labour. The compounds according to the invention may alsobe used in the treatment of small cell lung cancers; hyponatremicencephalopathies; pulmonary syndrome, Meniere's disease; glaucoma,cataracts; obesity; type II diabetes; atherosclerosis; Cushing'ssyndrome; insulin resistance; hypertriglyceridaemia; in post-operativetreatment, in particular after abdominal surgery.

[0205] The compounds according to the invention may also be used in thetreatment or prevention of all stress-related pathologies such asfatigue and its syndromes, ACTH-dependent disorders, cardiac disorders,pain, changes in gastric emptying, faecal excretion (colitis, irritablebowel syndrome, Crohn's disease), acid secretion, hyperglycaemia,immunosuppression, inflammatory processes (rheumatoid arthritis andosteoarthritis), multiple infections, cancers, asthma, psoriasis,allergies and various neuropsychiatric disorders such as anorexianervosa, bulimia, mood disorders, depression, anxiety, sleepingdisorders, panic attacks, phobias, obsession, pain-perception disorders(fibromyalgia), neurodegenerative diseases (Alzheimer's disease,Parkinson's disease, Huntington's disease), dependency on a substance,haemorrhagic stress, muscular spasms and hypoglycaemia. The compoundsaccording to the invention may also be used in the treatment orprevention of chronic stress states such as immunodepression, fertilitydisorders and dysfunctions of the hypothalamo-hypophyso-adrenal axis.

[0206] The compounds according to the invention may also be used aspsychostimulants, bringing about an increase in consciousness and inemotional reactivity towards the environment and facilitating adaptationthereto.

[0207] The compounds of formula (I) above, or a pharmaceuticallyacceptable salt, solvate and/or hydrate thereof, may be used at dailydoses of from 0.01 to 100 mg per kilo of body weight of the mammal to betreated, preferably at daily doses of from 0.1 to 50 mg/kg. In man, thedose may preferably range from 0.1 to 4000 mg per day, more particularlyfrom 0.5 to 1000 mg depending on the age of the individual to be treatedor the type of treatment: prophylactic or curative.

[0208] For their use as medicinal products, the compounds of formula (I)are generally administered in dosage units. The said dosage units arepreferably formulated in pharmaceutical compositions in which the activeprinciple is mixed with one or more pharmaceutical excipients.

[0209] Thus, according to another of its aspects, the present inventionrelates to pharmaceutical compositions containing, as active principle,a compound of formula (I), or a pharmaceutically acceptable salt,solvate and/or hydrate thereof.

[0210] In the pharmaceutical compositions of the present invention fororal, sublingual, inhaled, subcutaneous, intramuscular, intravenous,transdermal, local or rectal administration, the active principles maybe administered in unit administration forms, mixed with conventionalpharmaceutical supports, to animals and humans. The appropriate unitadministration forms comprise oral forms such as tablets, gel capsules,powders, granules and oral solutions or suspensions, sublingual andbuccal administration forms, aerosols, topical administration forms,implants, subcutaneous, intramuscular, intravenous, intranasal orintraocular administration forms and rectal administration forms.

[0211] When a solid composition is prepared in the form of tablets orgel capsules, a mixture of pharmaceutical excipients which may becomposed of diluents such as, for example, lactose, microcrystallinecellulose, starch, dicalcium phosphate, binders such as, for example,polyvinylpyrrolidone or hydroxypropylmethylcellulose, disintegratingagents such as crosslinked polyvinylpyrrolidone or crosslinkedcarboxymethylcellulose, flow agents such as silica, talc, lubricantssuch as magnesium stearate, stearic acid, glyceryl tribehenate or sodiumstearyl fumarate is added to the active principle, which may or may notbe micronized.

[0212] Wetting agents or surfactants such as sodium lauryl sulphate,polysorbate 80 and poloxamer 188 may be added to the formulation.

[0213] The tablets may be prepared by various techniques, directtableting, dry granulation, wet granulation, or hot-melt.

[0214] The tablets may be plain or sugar-coated (for example coated withsucrose) or coated with various polymers or other suitable materials.

[0215] The tablets may have an immediate, delayed or sustained releaseby producing polymer matrices or by using specific polymers in the filmcoating.

[0216] The gel capsules may be hard or soft, and film-coated orotherwise, so as to have immediate, sustained or delayed activity (forexample via an enteric form).

[0217] They may contain not only a solid formulation formulated as abovefor the tablets but also liquid or semi-solid formulations.

[0218] A preparation in the form of a syrup or elixir may contain theactive principle together with a sweetener, preferably a calorie-freesweetener, methylparaben and propylparaben as antiseptic, as well as aflavouring and a suitable colorant.

[0219] The water-dispersible powders or granules may contain the activeprinciple as a mixture with dispersants, wetting agents or suspendingagents, such as polyvinylpyrrolidone, as well as with sweeteners orflavour enhancers.

[0220] For rectal administration, use is made of suppositories which areprepared with binders that melt at the rectal temperature, for examplecocoa butter or polyethylene glycols.

[0221] Aqueous suspensions, isotonic saline solutions or sterileinjectable solutions which contain pharmacologically compatibledispersants and/or solubilizing agents, for example propylene glycol,are used for parenteral, intranasal or intraocular administration.

[0222] Thus, to prepare an aqueous solution for intravenous injection, aco-solvent such as, for example, an alcohol such as ethanol or a glycolsuch as polyethylene glycol or propylene glycol, and a hydrophilicsurfactant such as polysorbate 80 or poloxamer 188 may be used. Toprepare an oily solution for intramuscular injection, the activeprinciple may be dissolved with a triglyceride or a glycerol ester.

[0223] Creams, ointments, gels, eye drops and sprays may be used forlocal administration.

[0224] Patches in multilayer form or in a form with a reservoir in whichthe active principle may be in alcoholic solution, and sprays may beused for transdermal administration.

[0225] An aerosol containing, for example, sorbitan trioleate or oleicacid as well as trichlorofluoromethane, dichlorofluoromethane,dichlorotetrafluoroethane, freon substitutes or any other biologicallycompatible propellent gas is used for administration by inhalation; asystem containing the active principle alone or combined with anexcipient, in powder form, may also be used.

[0226] The active principle may also be in the form of a complex with acyclodextrin, for example α,β,γ-cyclodextrin or2-hydroxypropyl-β-cyclodextrin.

[0227] The active principle may also be formulated in the form ofmicrocapsules or microspheres, optionally with one or more supports oradditives.

[0228] Among the sustained-release forms that are useful in the case ofchronic treatments, it is possible to use implants. These may beprepared in the form of an oily suspension or in the form of asuspension of microspheres in an isotonic medium.

[0229] In each dosage unit, the active principle of formula (I) ispresent in the amounts tailored to the daily doses envisaged. Ingeneral, each dosage unit is appropriately tailored according to thedosage and the type of administration planned, for example tablets, gelcapsules and the like, sachets, ampules, syrups and the like, and drops,such that such a dosage unit contains from 0.1 to 1000 mg of activeprinciple, preferably from 0.5 to 250 mg which is to be administered oneto four times a day.

[0230] Although these dosages are examples of average situations, theremay be particular cases in which higher or lower dosages areappropriate, and such dosages also form part of the invention. Accordingto the usual practice, the dosage which is appropriate for each patientis determined by the doctor according to the mode of administration,age, weight and response of the said patient.

[0231] The compositions of the present invention may contain, along withthe compounds of formula (I), or a pharmaceutically acceptable salt,solvate and/or hydrate thereof, other active principles which may beuseful in the treatment of the disorders or diseases mentioned above.

[0232] Thus, a subject of the present invention is also pharmaceuticalcompositions containing several active principles in combination, one ofwhich is a compound according to the invention.

[0233] Thus, according to the present invention, pharmaceuticalcompositions containing a compound according to the invention combinedwith a compound acting on the CRF receptors may be prepared.

[0234] The compounds according to the invention may also be used toprepare compositions for veterinary use.

[0235] The Preparations and Examples which follow illustrate theinvention without, however, limiting it.

[0236] The following abbreviations are used in the Preparations and inthe Examples:

[0237] ether: Diethyl ether

[0238] iso-ether: Diisopropyl ether

[0239] DMF: N,N-Dimethylformamide

[0240] THF: Tetrahydrofuran

[0241] DCM: Dichloromethane

[0242] EtOAc: Ethyl acetate

[0243] DIPEA: Diisopropylethylamine

[0244] TFA: Trifluoroacetic acid

[0245] Boc: tert-Butoxycarbonyl

[0246] Cbz: Benzyloxycarbonyl

[0247] BOP: Benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate

[0248] DCC: 1,3-Dicyclohexylcarbodiimide

[0249] HOBT: 1-Hydroxybenzotriazole hydrate

[0250] PS-Trisamine: Tris(2-aminoethyl)amine polystyrene 1% crosslinkedwith divinylbenzene, containing 3.62 millimol of amine function per gramof resin, sold by Argonaut Technologie.

[0251] m.p.: Melting point

[0252] RT: Room temperature

[0253] b.p.: Boiling point

[0254] HPLC: High performance liquid chromatography

[0255] The proton magnetic resonance (¹H NMR) spectra are recorded at200 MHz in DMSO-d₆, using the peak for DMSO-d₆ as reference. Thechemical shifts δ are expressed in parts per million (ppm). The signalsobserved are expressed as follows: s: singlet; bs: broad singlet; d:doublet; dd: doubled doublet; t: triplate; q: quartet; m: unresolvedpeak; mt: multiplet.

[0256] The mass spectra indicate the value MH⁺.

[0257] Preparations

[0258] Preparation of the Compounds of Formula (IV)

[0259] Preparation 1.1

[0260] 3,5-Dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0261] (IV): R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; Hal=Cl

[0262] A)5-Chloro-3-hydroxy-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0263] This compound is prepared according to the procedure disclosed inWO 95/18105. A solution of 2-methoxyphenylmagnesium bromide is preparedfrom 16 g of magnesium in 35 ml of ether and from a solution of 124 g of1-bromo-2-methoxybenzene in 175 ml of ether. This solution is addeddropwise, under an argon atmosphere, to a mixture of 30 g of5-chloro-1H-indole-2,3-dione in 250 ml of THF, cooled beforehand in abath of ice, and the mixture is then left stirring while allowing thetemperature to return to RT. After stirring for one hour at RT, thereaction mixture is poured slowly into saturated NH₄Cl solution and theTHF is evaporated off under vacuum. The precipitate formed isspin-filtered off and washed with iso-ether. 42 g of the expectedproduct are obtained and are used in the next step without furtherpurification.

[0264] B) 3,5-Dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0265] This compound is prepared according to the procedure disclosed inWO 95/18105. A mixture of 12.71 g of the compound obtained in thepreceding step in 105 ml of DCM is cooled to 0° C. and 5.3 ml ofpyridine are added, followed by 4.9 ml of thionyl chloride. Afterstirring for 30 minutes, water is added to the reaction mixture and theDCM is evaporated off under vacuum. The precipitate formed isspin-filtered off, washed three times with water and then three timeswith iso-ether and dried. 13.66 g of the expected product are obtainedand are used without further purification.

[0266] Preparation 1.2

[0267] 3-Bromo-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-2H-indol-2-one

[0268] (IV): R₁=Cl; R₂=H; R₃=Cl; R₄=H; Hal=Br

[0269] This compound is prepared according to the procedures disclosedin WO 95/18105 in steps A), B) and C) of Preparation 2.

[0270] Preparation 1.3

[0271] 3-Chloro-5-methyl-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0272] (IV): R₁=CH₃; R₂=H; R₃=OCH₃; R₄=H; Hal=Cl

[0273] A)5-Methyl-3-hydroxy-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0274] A solution of 2-methoxyphenylmagnesium bromide is prepared from6.8 g of magnesium in 15 ml of THF and from a solution of 52.5 g of1-bromo-2-methoxybenzene in 75 ml of THF. This solution is addeddropwise at RT, under an argon atmosphere, to a mixture of 8.9 g of5-methyl-1H-indole-2,3-dione in 80 ml of THF and is then refluxed for 3hours. After cooling to RT, saturated NH₄Cl solution is added to thereaction mixture, the resulting mixture is extracted three times withEtOAc and the combined organic phases are washed twice with water andwith saturated NaCl solution, dried over Na₂SO₄ and the solvent ispartially concentrated. The precipitate formed is spin-filtered off togive 9 g of the expected product.

[0275] B)3-Chloro-5-methyl-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0276] A mixture of 2 g of the compound obtained in the preceding stepin 15 ml of DCM is cooled to 0° C. and 0.82 ml of pyridine is added,followed by 0.76 ml of thionyl chloride. After stirring for 20 minutes,water is added to the reaction medium and the DCM is evaporated offunder vacuum. The aqueous phase is extracted with EtOAc and the organicphase is washed with water, with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. 1.5 g of theexpected product are obtained after crystallization from a DCM/iso-ethermixture.

[0277] Preparation 1.4

[0278]3-Chloro-3-(2-methoxyphenyl)-5-trifluoromethoxy-1,3-dihydro-2H-indol-2-one

[0279] (IV): R₁=OCF₃; R₂=H; R₃=OCH₃; R₄=H; Hal=Cl

[0280] A)3-Hydroxy-3-(2-methoxyphenyl)-5-trifluoromethoxy-1,3-dihydro-2H-indol-2-one

[0281] A solution of 2-methoxyphenylmagnesium bromide is prepared from1.9 g of magnesium in 4 ml of ether and from a solution of 14.54 g of1-bromo-2-methoxybenzene in 21 ml of ether. This solution is addeddropwise, under an argon atmosphere, to a mixture of 5 g of5-trifluoromethoxy-1H-indole-2,3-dione in 26 ml of THF, cooledbeforehand in an ice bath, and then heated at the reflux point of theether for 1 hour 30 minutes and allowed to cool to RT. The reactionmixture is poured slowly into saturated NH₄Cl solution and extractedwith EtOAc, the organic phase is washed with 5% K₂CO₃ solution, withwater and with saturated NaCl solution and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. 2.8 g of the expected productare obtained.

[0282] B)3-Chloro-3-(2-methoxyphenyl)-5-trifluoromethoxy-1,3-dihydro-2H-indol-2-one

[0283] A mixture of 2 g of the compound obtained in the preceding stepin 20 ml of DCM is cooled to 0° C., 0.7 g of pyridine is added, followedby 1.05 g of thionyl chloride and the mixture is stirred for 15 minutes.The reaction mixture is concentrated to a volume of 10 ml and thissolution is used in this form in Preparations 3.9 and 3.10.

[0284] Preparation 1.5

[0285]3,5-Dichloro-3-(2-methoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-one

[0286] (IV): R₁=Cl; R₂₌₆-CH₃; R₃=OCH₃; R₄=H; Hal=Cl

[0287] A) Ethyl 2-(2-methoxyphenyl)-2-oxoacetate

[0288] A solution of 27 g of 1-bromo-2-methoxybenzene in 270 ml of etheris cooled to −70° C., under an argon atmosphere, 90 ml of a 1.6 Msolution of n-butyllithium in pentane are added dropwise and the mixtureis then stirred for 45 minutes. 78 ml of diethyl oxalate are addedrapidly and the mixture is stirred while allowing the temperature toreturn to RT. After stirring for 1 hour at RT, saturated NH₄Cl solutionis added to the reaction mixture, the phases are separated by settling,the aqueous phase is extracted with ether, the combined organic phasesare washed with water, with saturated NaCl solution and dried overNa₂SO₄, and the solvents are evaporated off under vacuum. The excessdiethyl oxalate is removed by distillation under vacuum (b.p.=87° C. at2000 Pa). The resulting product is chromatographed on silica gel elutingwith a DCM/hexane mixture (50/50; v/v) and then with DCM. The productobtained is purified by distillation under vacuum. 13 g of the expectedproduct are obtained; b.p.=110° C. at 3 Pa.

[0289] B)5-Chloro-3-hydroxy-3-(2-methoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-one

[0290] a) Tert-Butyl 4-chloro-3-methylphenyl-carbamate

[0291] A mixture of 10 g of 4-chloro-3-methylaniline and 15.26 g ofdi-tert-butyl dicarbonate in 50 ml of dioxane is stirred for 24 hours atRT. The reaction mixture is concentrated under vacuum and the residue ischromatographed on silica gel, eluting with a gradient of DCM/hexanemixture of from (50/50; v/v) to (70/30; v/v). 5.6 g of the expectedproduct are obtained and are used without further purification.

[0292] b) A solution of 5 g of tert-butyl4-chloro-3-methylphenylcarbamate in 45 ml of ether is cooled to −70° C.,under an argon atmosphere, 30 ml of a 1.5 M solution oftert-butyllithium in pentane are added dropwise, the mixture is stirredfor 1 hour while allowing the temperature to rise to −10° C., and isstirred for 1 hour 45 minutes at −10° C. The reaction mixture is cooledto −70° C., a solution of 5 g of the compound obtained in step A in 25ml of THF is added dropwise and the mixture is stirred for 1 hour whileallowing the temperature to rise to −30° C., and is then stirredovernight while allowing the temperature to return to RT. SaturatedNa₄Cl solution is added to the reaction mixture, the THF is evaporatedoff, the resulting aqueous phase is extracted three times with EtOAc,the organic phase is washed with water, with saturated NaCl solution anddried over Na₂SO₄, the solvent is partially evaporated off and thecrystalline product is spin-filtered off. 2.6 g of the expected productare obtained; m.p.=254-256° C.

[0293] C)3,5-Dichloro-3-(2-methoxyphenyl)-6-methyl-1,3-dihydro-2H-indol-2-one

[0294] A mixture of 1.25 g of the compound obtained in step B in 20 mlof DCM is cooled to 0° C., 0.51 ml of pyridine is added, followed by0.47 ml of thionyl chloride, and, after allowing the temperature toreturn to RT, the mixture is stirred for 1 hour. Water and DCM are addedto the reaction mixture and, after separation of the phases by settling,the organic phase is washed four times with water, dried over Na₂SO₄ andconcentrated under vacuum to a volume of 20 ml, and this solution isused in this form in Preparations 3.11 and 3.12 or 3.31.

[0295] Preparation 1.6

[0296]3-Chloro-3-(2-chlorophenyl)-5,6-dimethyl-1,3-dihydro-2H-indol-2-one

[0297] (IV): R₁=CH₃; R₂=6-CH₃; R₃=Cl; R₄=H; Hal=Cl

[0298] A) N-(3,4-Dimethylphenyl)-D,L-2-chloromandel-amide

[0299] A mixture of 50 g of 3,4-dimethylaniline and 76.5 g ofD,L-2-chloromandelic acid in 250 ml of 1,2-dichlorobenzene is heated at227° C. for 7 hours, while removing the water formed with the aid ofDean-Stark apparatus. The reaction mixture is concentrated under vacuumto half its volume and is left to crystallize at RT. The crystallineproduct formed is spin-filtered and washed with iso-ether. 89.42 g ofthe expected product are obtained, a sample of which is recrystallizedfrom a DCM/iso-ether mixture; m.p.=172-173° C.

[0300] B) 3-(2-Chlorophenyl)-5,6-dimethyl-1,3-dihydroindol-2-one

[0301] 100 ml of 95% sulphuric acid are cooled to −10° C., 12 ml offuming sulphuric acid (65% oleum) are added dropwise over 30 minutes andthe mixture is stirred while allowing the temperature to rise to +10° C.The mixture is cooled again to 0° C., 23.8 g of the compound obtained inthe preceding stage are added portionwise over 10 minutes and theresulting mixture is stirred while allowing the temperature to rise, thetemperature stabilizing at 29° C. After stirring for 2 hours at RT, thereaction mixture is poured onto ice and the precipitate formed isspin-filtered off. The precipitate is dissolved in 1000 ml of DCM and200 ml of THF, the pH is brought to 2 by adding solid K₂CO₃, thismixture is filtered and the filtrate is concentrated under vacuum. Theresidue is chromatographed on silica gel, eluting with a gradient ofDCM/EtOAc/THF mixture of from (90/10/5; v/v/v) to (80/20/5; v/v/v). 7.72g of the expected product are obtained; m.p.=231° C.

[0302] C)3-(2-Chlorophenyl)-3-hydroxy-5,6-dimethyl-1,3-dihydroindol-2-one

[0303] 0.65 g of 60% sodium hydride in oil is added at RT, under anargon atmosphere, to a solution of 4 g of the compound obtained in thepreceding step in 70 ml of THF. After the evolution of gas has ceased,1.7 ml of dimethyl disulphide are added and a stream of air is bubbledinto the reaction mixture for 4 hours at RT. The reaction mixture ispoured into water, the THF is concentrated under vacuum, the aqueousphase is extracted with EtOAc, the organic phase is washed with water,with saturated NaCl solution and dried over Na₂SO₄, the solvent ispartially concentrated under vacuum and the crystalline product formedis spin-filtered off. 3.3 g of the expected product are obtained;m.p.=251-253° C.

[0304] D)3-Chloro-3-(2-chlorophenyl)-5,6-dimethyl-1,3-dihydro-2H-indol-2-one

[0305] A suspension of 1 g of the compound obtained in the precedingstep in 7 ml of DCM is cooled to 0° C., 0.4 ml of pyridine is added,followed by 0.37 ml of thionyl chloride, and the mixture is stirred for30 minutes. The reaction mixture is diluted by adding 30 ml of DCM, theorganic phase is washed with 20 ml of water and dried over Na₂SO₄, andthe solvent is partially concentrated under vacuum at a temperaturebelow 40° C. This solution is used in this form in Preparations 3.13 and3.14.

[0306] Preparation 1.7

[0307] 3,5-Dichloro-3-(2,3-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0308] (IV): R₁=Cl; R₂=H; R₃=OCH₃; R₄=3-OCH₃; Hal=Cl

[0309] A) Ethyl 2-(2,3-dimethoxyphenyl)-2-oxoacetate

[0310] A mixture of 27.6 g of 1,2-dimethoxybenzene in 160 ml of ether iscooled to −40° C., 250 ml of 1.6 M solution of n-butyllithium in hexaneare added dropwise and the mixture is then stirred for 24 hours whileallowing the temperature to return to RT. The reaction mixture is cooledto −20° C., 136 ml of diethyl oxalate are added quickly and the mixtureis stirred while allowing the temperature to return to RT. Afterstirring for 30 minutes at RT, the reaction mixture is poured intosaturated NH₄Cl solution, the phases are separated by settling, theaqueous phase is extracted with ether, the combined organic phases arewashed twice with water and dried over Na₂SO₄, and the solvents areevaporated off under vacuum. The excess diethyl oxalate is removed bydistillation under vacuum (b.p.=90° C. at 2400 Pa). The resulting crudeproduct is chromatographed on silica gel, eluting with aheptane/iso-ether mixture (90/10; v/v). 25 g of the expected product areobtained and are used in the next step without further purification.

[0311] B)5-Chloro-3-hydroxy-3-(2,3-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0312] a) tert-Butyl 4-chlorophenylcarbamate

[0313] A mixture of 12.7 g of 4-chloroaniline and 22 g of di-tert-butyldicarbonate in 60 ml of dioxane is stirred at RT for 24 hours. Thereaction mixture is concentrated under vacuum, the residue is taken upin pentane and the precipitate formed is spin-filtered off and dried.22.5 g of the expected product are obtained.

[0314] b) A mixture of 11.4 g of tert-butyl 4-chlorophenylcarbamate in100 ml of ether is cooled to −40° C., under an atmosphere of drynitrogen, 80 ml of a 1.5 M solution of tert-butyllithium in pentane areadded dropwise and the mixture is stirred at −20° C. for 3 hours. Thereaction mixture is cooled to −40° C., a solution of 14 g of thecompound obtained in step A in 50 ml of THF is added over one hour andthe mixture is stirred for 4 days at RT. The reaction mixture is pouredinto saturated NH₄Cl solution and the precipitate formed isspin-filtered off and dried. 10.2 g of the expected product are obtainedand are used in the next step without further purification.

[0315] C)3,5-Dichloro-3-(2,3-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0316] 0.8 ml of pyridine and then 1.2 ml of thionyl chloride are added,at RT, to a mixture of 2 g of the compound obtained in step B in 50 mlof DCM, and the mixture is stirred until dissolution is complete. Thereaction mixture is washed with 1N HCl solution and then twice withwater and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is chromatographed on silica gel, eluting with aDCM/EtOAc mixture (95/5; v/v). 1.2 g of the expected product areobtained and are used without further purification.

[0317] Preparation 1.8

[0318]3,5-Dichloro-3-(2-methoxyphenyl)-6-trifluoromethyl-1,3-dihydro-2H-indol-2-one

[0319] (IV): R₁=Cl; R₂=6-CF₃; R₃=OCH₃; R₄=H; Hal=Cl

[0320] A)5-Chloro-3-hydroxy-3-(2-methoxyphenyl)-6-trifluoromethyl-1,3-dihydro-2H-indol-2-one

[0321] a) tert-Butyl 4-chloro-3-trifluoromethyl-phenylcarbamate

[0322] This compound is prepared according to the procedure described instep B a) of Preparation 1.5, from 4-chloro-3-trifluoromethylaniline anddi-tert-butyl dicarbonate in dioxane. The expected product is obtainedin the form of an oil which solidifies; m.p.=90° C.

[0323] b) A solution of 4 g of tert-butyl4-chloro-3-trifluoromethylphenylcarbamate in 30 ml of ether is cooled to−70° C., under an argon atmosphere, 22 ml of a 1.5 M solution oftert-butyllithium in pentane are added dropwise and the mixture isstirred for 1 hour while allowing the temperature to rise to −10° C. andis stirred for 2 hours 30 minutes at −10° C. The reaction mixture iscooled to −70° C., a solution of 3.05 g of the compound obtained in stepA of Preparation 1.5 in 15 ml of THF is added dropwise and the mixtureis stirred for 1 hour while allowing the temperature to rise to −30° C.and then for 16 hours while allowing the temperature to return to RT.Saturated NH₄Cl solution is added to the reaction mixture, the ether andTHF are evaporated off, the resulting aqueous phase is extracted withEtOAc, the organic phase is washed with water, with saturated NaClsolution and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is chromatographed on silica gel, eluting with DCMand then with a DCM/EtOAc mixture (90/10; v/v). 1.48 g of the expectedproduct are obtained after crystallization from an iso-ether/hexanemixture; m.p.=230-231° C.

[0324] B)3,5-Dichloro-3-(2-methoxyphenyl)-6-trifluoromethyl-1,3-dihydro-2H-indol-2-one

[0325] A suspension of 1.3 g of the compound obtained in step A in 8 mlof DCM is cooled to 0° C., 0.43 ml of pyridine and then 0.4 ml ofthionyl chloride are added and the mixture is stirred for 15 minutes.The reaction mixture is washed three times with water, the organic phaseis dried over Na₂SO₄ and the solvent is partially evaporated off undervacuum down to a volume of 10 ml. This solution is used in this form inPreparations 3.17 and 3.18.

[0326] Preparation 1.9

[0327]3,5-Dichloro-3-(2-chlorophenyl)-6-methoxy-1,3-dihydro-2H-indol-2-one

[0328] (IV): R₁=Cl; R₂=6-OCH₃; R₃=Cl; R₄=H; Hal=Cl

[0329] A) 4-Chloro-3-methoxyaniline

[0330] A mixture of 36 g of 2-chloro-5-nitroanisole and Raney® nickel in150 ml of MeOH and 200 ml of THF is hydrogenated in Par apparatus for 4hours, at 35° C. and at a pressure of 1.3 bar. The catalyst is filteredoff on Celite® and the filtrate is concentrated under vacuum. 28 g ofthe expected product are obtained, and are used without furtherpurification.

[0331] B) N-(4-Chloro-3-methoxyphenyl)-D,L-2-chloromandelamide

[0332] A mixture of 28 g of the compound obtained in the preceding stepand 33.13 g of D,L-2-chloromandelic acid in 128 ml of1,2-dichlorobenzene is heated at 230° C. for 4 hours, while removing thewater formed with the aid of Dean-Stark apparatus. The reaction mixtureis partially concentrated under vacuum and left to crystallize. Thecrystalline product formed is spin-filtered off and washed withiso-ether. 40 g of the expected product are obtained.

[0333] C)5-Chloro-3-(2-chlorophenyl)-6-methoxy-1,3-dihydro-2H-indol-2-one

[0334] 40 g of the compound obtained in the preceding step are addedrapidly to 550 g of polyphosphoric acid, the mixture is then heated at60° C. for 8 hours and is left stirring overnight while allowing thetemperature to return to RT. Ice-water is added to the reaction mixtureand the precipitate formed is spin-filtered off and washed with water.The precipitate is taken up in EtOAc and, after slurrying, the whiteproduct obtained is spin-filtered off and washed with iso-ether. 17.2 gof the expected product are obtained; m.p.=243-247° C.

[0335] D)5-Chloro-3-(2-chlorophenyl)-3-hydroxy-6-methoxy-1,3-dihydro-2H-indol-2-one

[0336] 2.56 g of 60% sodium hydride in oil are added at RT, under anargon atmosphere, to a solution of 17.2 g of the compound obtained inthe preceding step in 220 ml of THF. After the evolution of gas hasceased, 6.85 g of dimethyl disulphide are added, air is bubbled into thereaction mixture and the mixture is stirred at RT for 72 hours. Water isadded to the reaction mixture, the THF is evaporated off under vacuum,the remaining aqueous phase is extracted with EtOAc, the organic phaseis washed with water, with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The productobtained is dissolved in DCM, the solvent is partially concentrated, theproduct is allowed to crystallize and the crystalline product formed isspin-filtered off. 6 g of the expected product are obtained;m.p.=237-240° C.

[0337] E)3,5-Dichloro-3-(2-chlorophenyl)-6-methoxy-1,3-dihydro-2H-indol-2-one

[0338] A suspension of 1.5 g of the compound obtained in the precedingstep in 20 ml of DCM is cooled in an ice bath, 0.375 ml of pyridine andthen 0.33 ml of thionyl chloride are added and the mixture is stirredfor 30 minutes. At the end of the reaction, a suspension of the expectedproduct which has precipitated in the DCM is obtained and thissuspension is used directly in Preparations 3.19 and 3.20.

[0339] Preparation 1.10

[0340]3,6-Dichloro-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

[0341] (IV): R₁=CH₃; R₂=6-Cl; R₃=OCH₃; R₄=H; Hal=Cl

[0342] A) 6-Chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one and4-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one

[0343] 8.5 ml of chlorine are introduced into 320 ml of DCM cooled to−70° C., followed by addition, over 20 minutes and at −70° C., of asolution of 24 ml of ethyl methylthioacetate in 60 ml of DCM, and themixture is stirred for 15 minutes at −70° C. A solution of 52.64 g of3-chloro-4-methylaniline in 100 ml of DCM is then added, at −70° C. andover 30 minutes, and is stirred for 1 hour 45 minutes at −70° C.Finally, 41.3 ml of triethylamine are added, at −70° C., and the mixtureis stirred for 1 hour while allowing the temperature to return to RT.The reaction mixture is washed twice with 250 ml of water, the organicphase is dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is taken up in a mixture of 600 ml of ether and 130ml of 2N HCl, and is stirred for 72 hours at RT. An insoluble product isfiltered off, the phases of the filtrate are allowed to separate bysettling, the organic phase is washed twice with water and dried overMgSO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with DCM and then with aDCM/EtOAc mixture (85/15; v/v). The mixture obtained isre-chromatographed on silica gel, eluting with DCM and then with aDCM/EtOAc mixture (95/5; v/v). The two isomers are separated.

[0344] 1.16 g of the less polar isomer, which is6-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one, are obtained,

[0345] 0.72 g of the more polar isomer, which is4-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one, is obtained.

[0346] E) 6-Chloro-5-methyl-1H-indole-2,3-dione

[0347] A mixture of 1.16 g of6-chloro-5-methyl-3-methylthio-1,3-dihydro-2H-indol-2-one obtained inthe preceding step and 0.681 g of N-chlorosuccinimide in 100 ml ofcarbon tetrachloride is refluxed for 1 hour. The reaction mixture isconcentrated under vacuum and the residue is taken up in a mixture of 80ml of THF and 20 ml of water and then refluxed for 16 hours. The THF isevaporated off under vacuum, the remaining aqueous phase is extractedwith EtOAc, the organic phase is washed with water, with saturated NaClsolution and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is chromatographed on silica gel, eluting with DCMand then with a gradient of DCM/EtOAc mixture down to (85/15; v/v).0.793 g of the expected product is obtained; m.p.=264° C.

[0348] C)6-Chloro-3-hydroxy-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

[0349] A solution of 2-methoxyphenylmagnesium bromide is prepared from0.687 g of magnesium in 1.5 ml of ether and from a solution of 5.35 g of1-bromo-2-methoxybenzene in 7.55 ml of ether. This solution is addeddropwise, under an argon atmosphere, to a mixture of 1.4 g of thecompound obtained in the preceding step in 14 ml of THF cooledbeforehand in an ice bath, and the mixture is then stirred whileallowing the temperature to return to RT. After stirring for 1 hour atRT, the reaction mixture is poured slowly into saturated NH₄Cl solution,the THF is evaporated off under vacuum, the aqueous phase is extractedwith EtOAc, the organic phase is washed with water, with saturated NaClsolution and dried over Na₂SO₄ and the EtOAc is evaporated off undervacuum. The residue is chromatographed on silica gel, eluting with DCMand then with a DCM/MeOH mixture (98/2; v/v). 1.6 g of the expectedproduct are obtained after crystallization from a THF/MeOH mixture;m.p.=266° C.

[0350] D)3,6-Dichloro-3-(2-methoxyphenyl)-5-methyl-1,3-dihydro-2H-indol-2-one

[0351] A suspension of 2.5 g of the compound obtained in the precedingstep in 15 ml of DCM is cooled in an ice bath, 1 ml of pyridine and then1.09 ml of thionyl chloride are added and the mixture is stirred for 2hours. The reaction mixture is partially concentrated under vacuum downto a volume of 10 ml and this solution is used in this form inPreparations 3.21 and 3.22.

[0352] Preparation 1.11

[0353]3-Bromo-5,6-dichloro-3-(2-chlorophenyl)-1,3-dihydro-2H-indol-2-one

[0354] (IV): R₁=Cl; R₂=6-Cl; R₃=Cl; R₄=H; Hal=Br

[0355] This compound is prepared according to the procedures disclosedin WO 95/18105 in steps A), B) and C) of Preparation 72.

[0356] Preparation 1.12

[0357] 3,5-Dichloro-3-(2-ethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0358] (IV): R₁=Cl; R₂=H; R₃=OCH₂CH₃; R₄=H, Hal=Cl

[0359] A) 1-Bromo-2-ethoxybenzene

[0360] A mixture of 17.5 g of 2-bromophenol, 66 ml of diethyl sulphateand 170 ml of 10% NaOH solution is refluxed for 2 hours. After coolingthe reaction mixture to RT, it is extracted with EtOAc, the organicphase is washed with 2N NaOH solution and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. 19.6 g of the expected productare obtained.

[0361] B)5-Chloro-3-(2-ethoxyphenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

[0362] A solution of 2-ethoxyphenylmagnesium bromide is prepared from2.2 g of magnesium in 10 ml of ether and from a solution of 16.5 g ofthe compound obtained in the preceding step in 40 ml of ether. Thissolution is added dropwise and under a nitrogen atmosphere to a mixtureof 5 g of 5-chloro-1H-indole-2,3-dione in 20 ml of THF, while keepingthe temperature of the reaction medium below 35° C. After stirring for 2hours at RT, the reaction mixture is poured into 200 ml of 2N HCl, themixture is extracted with EtOAc, the organic phase is dried over Na₂SO₄and the solvents are evaporated off under vacuum. The residue is takenup in hot iso-ether and left to crystallize. The crystalline productformed is spin-filtered off, washed with iso-ether and dried. 5.7 g ofthe expected product are obtained; m.p.=251° C.

[0363] C) 3,5-Dichloro-3-(2-ethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0364] 1 ml of thionyl chloride is added, at RT, to a mixture of 3 g ofthe compounds obtained in the preceding step and 2 ml of pyridine in 50ml of DCM, and the mixture is stirred for 1 hour at RT. The reactionmixture is chromatographed on silica gel, eluting with DCM. 2.4 g of theexpected product are obtained after crystallization from iso-ether;m.p.=198° C.

[0365] Preparation 1.13

[0366]3,5-Dichloro-3-(2-trifluoromexothyphenyl)-1,3-dihydro-2H-indol-2-one

[0367] (IV): R₁=Cl; R₂=H; R₃=OCF₃; R₄=H, Hal=Cl

[0368] A)5-Chloro-3-hydroxy-3-(2-trifluoromethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0369] A solution of 25 g of 1-bromo-2-trifluoromethoxybenzene in 130 mlof ether is added dropwise to a mixture of 2.8 g of magnesium in 20 mlof ether, and once the refluxing has started it is maintained. At theend of the addition the mixture is refluxed for 1 hour. A mixture of 7.5g of 5-chloro-1H-indole-2,3-dione in 100 ml of THF is then added, at atemperature below 40° C., followed by refluxing for 1 hour. Aftercooling to RT, the reaction mixture is poured into an ice/concentratedHCl mixture, the resulting mixture is extracted with EtOAc, the organicphase is washed with water, with 1N NaOH solution and dried over Na₂SO₄,and the solvent is evaporated under vacuum. 6.5 g of the expectedproduct are obtained after crystallization from a DCM/iso-ether mixture(20/80; v/v); m.p.=214° C.

[0370] B)3,5-Dichloro-3-(2-trifluoromethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0371] 0.7 ml of thionyl chloride is added, at a temperature below 20°C., to a mixture of 2.7 g of the compound obtained in the preceding stepand 1 ml of pyridine in 20 ml of DCM, and the mixture is stirred for 1hour. The reaction mixture is washed twice with water, the organic phaseis dried over Na₂SO4 and the solvent is evaporated off under vacuum. 1.8g of the expected product are obtained after crystallization fromiso-ether; m.p.=185° C.

[0372] Preparation 1.14

[0373] 3,5-Dichloro-3-(2,3-difluorophenyl)-1,3-dihydro-2H-indol-2-one

[0374] (IV): R₁=Cl; R₂=H; R₃=F; R₄=3-F; Hal=Cl

[0375] A)5-Chloro-3-(2,3-difluorophenyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

[0376] A solution of 5.6 g of 1,2-difluorobenzene in 50 ml of ether iscooled to −10° C., 31 ml of a 1.6 M solution of n-butyllithium in hexaneare added dropwise and the mixture is stirred at −10° C. for 2 hours.The reaction mixture is cooled to −50° C., a solution of 4 g of5-chloro-1H-indole-2,3-dione in 40 ml of THF is added and the resultingmixture is stirred for 12 hours, while allowing the temperature toreturn to RT. The reaction mixture is poured into a concentratedHCl/ice/water mixture, the resulting mixture is extracted with EtOAc,the organic phase is washed with 1N NaOH solution, with water and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. 2.8 g ofthe expected product are obtained after crystallization from iso-ether;m.p.=248° C.

[0377] B) 3,5-Dichloro-3-(2,3-difluorophenyl)-1,3-dihydro-2H-indol-2-one

[0378] 0.9 ml of thionyl chloride is added to a mixture of 2.8 g of thecompound obtained in the preceding step and 1 ml of pyridine in 30 ml ofDCM, and the mixture is stirred for 1 hour at RT. The reaction mixtureis washed twice with water and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on silicagel, eluting with DCM. 0.9 g of the expected product is obtained.

[0379] Preparation 1.15

[0380] 3,5-Dichloro-3-(2,4-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0381] (IV): R₁=Cl; R₂=H; R₃=OCH₃; R₄=4-OCH₃; Hal=Cl

[0382] A)5-Chloro-3-hydroxy-3-(2,4-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0383] A solution of 2,4-dimethoxyphenylmagnesium bromide is preparedfrom 2.2 g of magnesium in 10 ml of THF and from a solution of 18 g of1-bromo-2,4-dimethoxybenzene in 40 ml of THF. This solution is addeddropwise to a mixture of 5 g of 5-chloro-1H-indole-2,3-dione in 50 ml ofTHF at a temperature of 30° C., and the mixture is then refluxed for 2hours. The reaction mixture is cooled to RT and poured into saturatedNH₄Cl solution, this mixture is extracted with EtOAc, the organic phaseis washed with water and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. 7.2 g of the expected product are obtainedafter crystallization from hot iso-ether.

[0384] B)3,5-Dichloro-3-(2,4-dimethoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0385] A mixture of 2.5 g of the compound obtained in the preceding stepand 0.6 ml of pyridine in 20 ml of DCM is cooled to a temperature below10° C., 0.6 ml of thionyl chloride is added dropwise and the mixture isstirred for 15 minutes. The reaction mixture is washed twice with waterand dried over Na₂SO₄, and the solvent is evaporated off under vacuum.The expected product is obtained, and is used in this form inPreparations 3.38 and 3.39.

[0386] Preparation 1.16

[0387] 3,5-Dichloro-3-(1,3-benzodioxol-4-yl)-1,3-dihydro-2H-indol-2-one

[0388] (IV): R₁=Cl; R₂=H; R₃+R₄ 2,3-O—CH₂—O—; Hal=Cl

[0389] A) 4-Bromo-1,3-benzodioxol

[0390] This compound is prepared according to the process disclosed inTetrahedron Lett., 1995, 36, 6413-6414.

[0391] B)5-Chloro-3-(1,3-benzodioxol-4-yl)-3-hydroxy-1,3-dihydro-2H-indol-2-one

[0392] A solution of 1,3-benzodioxol-4-ylmagnesium bromide is preparedfrom 0.85 g of magnesium in 10 ml of THF and from a solution of 6.7 g ofthe compound obtained in the preceding step in 40 ml of THF. Thissolution is added dropwise and at a temperature below 40° C. to amixture of 3 g of 5-chloro-1H-indole-2,3-dione in 50 ml of THF and theresulting mixture is then stirred for 1 hour. The reaction mixture ispoured into saturated NH₄Cl solution, the resulting mixture is extractedwith EtOAc, the organic phase is washed with water and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. 1.12 g of theexpected product are obtained after crystallization from DCM; m.p.=271°C.

[0393] C)3,5-Dichloro-3-(1,3-benzodioxol-4-yl)-1,3-dihydro-2H-indol-2-one

[0394] 0.3 ml of thionyl chloride is added, at a temperature below 25°C., to a mixture of 1.1 g of the compound obtained in the preceding stepand 0.4 ml of pyridine in 20 ml of DCM, and the mixture is stirred for30 minutes. The reaction mixture is washed twice with water, the organicphase is dried over Na₂SO₄ and the solvent is evaporated off undervacuum. 0.62 g of the expected product is obtained after crystallizationfrom DCM; m.p.=241° C.

[0395] Preparation 1.17

[0396] 3,5,6-Trichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0397] (IV): R₁=Cl; R₂=6-Cl; R₃=OCH₃; R₄=H; Hal=Cl

[0398] A) 5,6-Dichloro-1H-indole-2,3-dione

[0399] This compound is prepared according to the procedure disclosed inJ. Am. Chem. Soc., 1946, 68, 2697-2703 or according to the proceduredisclosed in J. Org. Chem., 1952, 17, 149-156.

[0400] B)5,6-Dichloro-3-hydroxy-3-(2-methxyphenyl)-1,3-dihydro-2H-indol-2-one

[0401] 5.57 g of 1-bromo-2-methoxybenzene are added dropwise to asuspension of 0.72 g of magnesium in 15 ml of ether containing a fewcrystals of iodine, and the refluxing is maintained once it has started.At the end of the addition, the mixture is refluxed for 2 hours. Asuspension of 2.7 g of 5,6-dichloro-1H-indole-2,3-dione in 30 ml of THFis then added and this mixture is refluxed for 30 minutes. After coolingto RT, the reaction mixture is poured into a water/ice/concentrated HClmixture, the resulting mixture is extracted with EtOAc, the organicphase is dried over Na₂SO₄ and the solvent is evaporated off undervacuum. The residue is slurried in hot iso-ether and the precipitateformed is spin-filtered off and washed with ether. 3 g of the expectedproduct are obtained.

[0402] C) 3,5,6-Trichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one

[0403] A suspension of 1.5 g of the compound obtained in the precedingstep in 30 ml of DCM is cooled in an ice bath, and 0.56 ml of pyridineis added, followed by 0.5 ml of thionyl chloride. After stirring for 1hour at RT, the reaction mixture is diluted by addition of DCM, theorganic phase is washed with water to neutral pH and dried over Na₂SO₄,and the solvent is evaporated off under vacuum. 1.5 g of the expectedproduct are obtained in the form of a foam which is used in this form.

[0404] Preparation of the compounds of formula (V).

[0405] Preparation 2.1 a)

[0406] (2S,4R)-4-Hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamideHydrochloride

[0407] (V), HCl: R₅=N(CH₃)₂; R₆=H

[0408] A)(2S,4R)-1-(tert-Butoxycarbonyl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide

[0409] A mixture of 11.2 g of(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acidin 50 ml of DCM is cooled to 0° C., 8.45 ml of DIPEA and then 21.2 g ofBOP are added and the resulting mixture is stirred for 10 minutes.Dimethylamine gas is then added by sparging and the mixture is stirredfor 3 hours at RT. The reaction mixture is partially concentrated undervacuum to a volume of 20 ml and an insoluble material is filtered off.The filtrate is chromatographed on silica gel, eluting with a DCM/MeOHmixture (94/6; v/v) and the product obtained is re-chromatographed onalumina, eluting with a DCM/MeOH mixture (96/4; v/v). 11.1 g of theexpected product are obtained.

[0410] B) (2S,4R)-4-Hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamideHydrochloride

[0411] A mixture of 6.9 g of the compound obtained in the preceding stepin 69 ml of a 4N solution of HCl in ether is stirred for 2 hours at RT.The reaction mixture is concentrated under vacuum, the residue is takenup in ether and the solvent is evaporated off under vacuum, thisoperation being repeated several times. 4 g of the expected product areobtained.

[0412] Preparation 2.1 b)

[0413] (2S,4R)-4-Hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamideTrifluoroacetate

[0414] (V), CF₃COOH: R₅=N(CH₃)₂; R₆=H

[0415] A solution of 2.1 g of the compound obtained in step A ofPreparation 2.1 a) in 5 ml of DCM is cooled to 0° C., 10 ml oftrifluoroacetic acid are added and this mixture is stirred for 2 hoursat RT. The reaction mixture is concentrated under vacuum, the residue istaken up in DCM and the solvent is evaporated off under vacuum, thisoperation being repeated several times. The expected product isobtained, and is used directly in Preparations 3.1 and 3.2.

[0416] Preparation 2.2

[0417] (2S,4R)-2-(Azetidin-1-ylcarbonyl)-4-hydroxypyrrolidine

[0418] (V): R₅=

[0419] ; R₆=H.

[0420] A)(2S,4R)-1-(Benzyloxycarbonyl)-2-(azetidin-1-ylcarbonyl)-4-hydroxypyrrolidine

[0421] A solution of 5 g of(2S,4R)-(benzyloxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid in 50ml of DCM and 10 ml of DMF is prepared, 2.7 g of HOBT and then 4.15 g ofDCC are added and the resulting mixture is stirred for 10 minutes at RT.The reaction mixture is cooled to 0° C., 2 g of azetidine are added andthis mixture is stirred for 12 hours, while allowing the temperature toreturn to RT. The precipitate formed is filtered off, the filtrate iswashed twice with saturated Na₂CO₃ solution, the organic phase is driedover Na₂SO₄ and the solvent is evaporated off under vacuum. The oilobtained is chromatographed on silica gel, eluting with a DCM/MeOHmixture (95/5; v/v). 2.1 g of the expected product are obtained.

[0422] B) (2S,4R)-2-(Azetidin-1-ylcarbonyl)-4-hydroxypyrrolidine

[0423] 1.8 g of the compound obtained in the preceding step and 0.58 gof 10% palladium-on-charcoal in 80 ml of EtOH is hydrogenated overnightat RT and at atmospheric pressure. The catalyst is filtered off onCelite® and the filtrate is concentrated under vacuum. 0.9 g of theexpected product is obtained.

[0424] Preparation 2.3

[0425] (2S,4R)-4-Methoxy-N,N-dimethyl-2-pyrrolidinecarboxamideHydrochloride

[0426] (V), HCl: R₅=N(CH₃)₂; R₆=CH₃

[0427] A)(2S,4R)-1-(tert-Butoxycarbonyl)-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide

[0428] A solution of 6.5 g of the compound obtained in step A ofPreparation 2.1 a) in 70 ml of THF is cooled to 0° C., 1.2 g of 60%sodium hydride in oil are added portionwise and the mixture is stirredfor 30 minutes at 0° C. A solution of 2.35 ml of methyl iodide in 10 mlof THF is then added dropwise and the mixture is stirred for 2 hours,while allowing the temperature to return to RT. 5 drops of water areadded and the reaction mixture is neutralized by addition ofconcentrated HCl and is concentrated under vacuum. The residual water isremoved azeotropically by addition of benzene and the resulting mixtureis concentrated under vacuum. The residue is chromatographed on silicagel, eluting with a DCM/MeOH mixture (96/4; v/v). 6.1 g of the expectedproduct are obtained.

[0429] B) (2S,4R)-4-Methoxy-N,N-dimethyl-2-pyrrolidinecarboxamidehydrochloride

[0430] A mixture of 6.1 g of the compound obtained in the preceding stepand 65 ml of a 4N solution of HCl in ether is stirred for 2 hours. Thereaction mixture is concentrated under vacuum, the residue is taken upin DCM and the solvent is evaporated off under vacuum, this operationbeing repeated several times. 4.45 g of the expected product areobtained.

[0431] Preparation 2.4

[0432] (2S,4R)-4-Ethoxy-N,N-dimethyl-2-pyrrolidinecarboxamideTrifluoroacetate

[0433] (V), CF₃COOH: R₅=N(CH₃)₂; R₆=—CH₂CH₃

[0434] A)(2S,4R)-1-(tert-Butoxycarbonyl)-4-ethoxy-2-pyrrolidinecarboxylic Acid

[0435] 1.72 g of 60% sodium hydride in oil are added, under a nitrogenatmosphere, to a solution of 5 g of(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acidin 100 ml of THF, and the mixture is stirred for 45 minutes at RT. 3.27g of ethyl iodide are then added, the mixture is refluxed for 3 hoursand stirred for 18 hours while allowing the temperature to return to RT.The reaction mixture is concentrated under vacuum, the residue is takenup in 5% KHSO₄ solution and extracted with EtOAc, the organic phase isdried over Na₂SO₄ and the solvent is evaporated off under vacuum. 4.5 gof the expected product are obtained in the form of an oil.

[0436] B)(2S,4R)-1-(tert-Butoxycarbonyl)-4-ethoxy-N,N-dimethyl-2-pyrrolidinecarboxamide

[0437] 3.5 g of triethylamine and then 7.6 g of BOP are added to asolution of 4.5 g of the compound obtained in the preceding step in 100ml of DCM, and this mixture is stirred for 15 minutes at RT.Dimethylamine gas is then added by sparging and the mixture is stirredfor 3 hours at RT. The reaction mixture is concentrated under vacuum,the residue is extracted with EtOAc, the organic phase is washed with 5%Na₂CO₃ solution, with 5% KHSO₄ solution and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/MeOH mixture (95/5; v/v). 2 g of theexpected product are obtained in the form of an oil.

[0438] C) (2S,4R)-4-Ethoxy-N,N-dimethyl-2-pyrrolidinecarboxamideTrifluoroacetate

[0439] A solution of 2 g of the compound obtained in the preceding stepin 10 ml of DCM is cooled to 0° C., 10 ml of trifluoroacetic acid areadded and the mixture is stirred for 2 hours at RT. The reaction mixtureis concentrated under vacuum, the residue is taken up in DCM and thesolvent is evaporated off under vacuum, this operation being repeatedseveral times. 2 g of the expected product are obtained.

[0440] Preparation 2.5

[0441] (2S,4S)-4-Hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamideHydrochloride

[0442] (V), HCl: R₅=N(CH₃)₂; R₆=H

[0443] A)(2S,4S)-1-(tert-Butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic Acid

[0444] 13.2 g of di-tert-butyl dicarbonate are added to a mixture of 4 gof (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid in 50 ml of a 10%solution of triethylamine in methanol, and the mixture is then refluxedfor 45 minutes. The reaction mixture is concentrated under vacuum, theresidue is taken up in 40 ml of water and acidified to pH=2 by additionof concentrated HCl solution, the resulting mixture is extracted withEtOAc, the organic phase is dried over Na₂SO₄ and the solvent isevaporated off under vacuum. 7.5 g of the expected product are obtained.

[0445] B)(2S,4S)-1-(tert-Butoxycarbonyl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide

[0446] A mixture of 7.5 g of the compound obtained in the preceding stepin 100 ml of DCM is cooled to 4° C., 5.7 ml of DIPEA and then 14.4 g ofBOP are added and this mixture is stirred for 30 minutes at 4° C.Dimethylamine gas is then added by sparging for 10 minutes and themixture is stirred for 3 hours at RT. The reaction mixture isconcentrated under vacuum, the residue is extracted with EtOAc, theorganic phase is washed with 5% KHSO₄ solution, with 5% Na₂CO₃ solution,with saturated NaCl solution and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on silicagel, eluting with a DCM/MeOH mixture (93/7; v/v). 2.4 g of the expectedproduct are obtained.

[0447] C) (2S,4S)-4-Hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamideHydrochloride

[0448] A mixture of 2.4 g of the compound obtained in the preceding stepin 15 ml of a 4N solution of HCl in dioxane is stirred for 2 hours at 4°C. The reaction mixture is concentrated under vacuum and withoutheating, the residue is taken up in ether and the precipitate formed isspin-filtered off. 0.9 g of the expected product is obtained.

[0449] Preparation 2.6

[0450] Tert-Butyl2-[[(3R,5S)-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]acetate

[0451] (V): R₅=N(CH₃)₂; R₆=—CH₂COO—C(CH₃)₃

[0452] A)(2S,4R)-1-(Benzyloxycarbonyl)-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide

[0453] A mixture of 15 g of(2S,4R)-1-(benzyloxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid,7.64 g of HOBT and 11.65 g of DCC in 250 ml of DCM is stirred for 1 hourat RT. The reaction mixture is cooled on an ice bath, dimethylamine gasis added by sparging for 10 minutes and this mixture is stirred for 3hours at RT. An insoluble material is filtered off and the filtrate isconcentrated under vacuum. The residue is taken up in saturated Na₂CO₃solution and extracted with DCM, the organic phase is dried over Na₂SO₄and the solvent is evaporated off under vacuum. 13 g of the expectedproduct are obtained in the form of an oil.

[0454] B) Tert-Butyl2-[[(3R,5S)-1-[(Benzyloxycarbonyl)-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]acetate

[0455] A mixture of 5 g of the compound obtained in the preceding stepand 3 g of tetrabutylammonium hydrogen sulphate in 100 ml of benzene iscooled to 0° C., 50 ml of aqueous 50% NaOH solution are added, followedby dropwise addition of 5 g of tert-butyl bromoacetate, and this mixtureis stirred vigorously for 30 minutes. The reaction mixture is dilutedwith a benzene/DCM mixture, the phases are separated by settling, theorganic phase is dried over Na₂SO₄ and the solvents are evaporated offunder vacuum. The residue is chromatographed on silica gel, eluting withEtOAc. 6.3 g of the expected product are obtained in the form of an oil.

[0456] C) tert-Butyl2-[[(3R,5S)-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]acetate

[0457] A mixture of 6.3 g of the compound obtained in the preceding stepand 0.7 g of 10% palladium-on-charcoal in 200 ml of EtOAc ishydrogenated for 3 hours, at RT and under atmospheric pressure. Thecatalyst is filtered off on Celite and the filtrate is concentrated tohalf its volume under vacuum. A solution of the expected product isobtained, which is used in Preparations 3.43 and 3.44.

[0458] Preparation 2.7

[0459] (3R,5S)-5-[(Dimethylamino)carbonyl]-3-pyrrolidine3-(4-morpholinyl)propionate

[0460] (V):R₅=—N(CH₃)₂; R₆=—COCH₂CH₂

[0461] A)Benzyl(2S,4R)-4-(acryloyloxy)-2-[(dimethylamino)carbonyl]-1-pyrrolidinecarboxylate

[0462] A mixture of 5 g of the compound obtained in step A ofPreparation 2.6 and 2.31 g of triethylamine in 100 ml of DCM is cooledto 0° C., 1.6 ml of acryloyl chloride are added dropwise and the mixtureis stirred for 2 hours at 0° C. The reaction mixture is washed withwater and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. 5.5 g of the expected product are obtained in the form of an oil

[0463] B) Benzyl(2S,4R)-2-[(dimethylamino)carbonyl]-4-[[3-(4-morpholinyl)propanoyl]oxy]-1-pyrrolidinecarboxylate

[0464] 0.265 g of ferric chloride and then 2.13 g of morpholine areadded to a solution of 5.5 g of the compound obtained in the precedingstep in 100 ml of DCM, and the mixture is stirred for 18 hours at RT.The reaction mixture is washed with saturated Na₂SO₄ solution, thephases are separated by settling, the organic phase is dried over Na₂SO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with DCM and then with a DCM/MeOHmixture (94/6; v/v). 4.5 g of the expected product are obtained in theform of an oil.

[0465] C) (3R,5S)-5-[(Dimethylamino)carbonyl]-3-pyrrolidine3-(4-morpholinyl)propionate

[0466] A mixture of 4.2 g of the compound obtained in the preceding stepand 0.45 g of 10% palladium-on-charcoal in 200 ml of EtOAc ishydrogenated for 3 hours, at RT and at atmospheric pressure. Thecatalyst is filtered off on Celite and the filtrate is concentrated tohalf its volume under vacuum. A solution of the expected product isobtained, which is used in this form in Preparation 3.45.

[0467] Preparation of the Compounds of Formula (II).

[0468] Preparations 3.1 and 3.2

[0469](2S,4R)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0470] (II): R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=H

[0471] The compound obtained in Preparation 2.1 b) is dissolved in 5 mlof DCM, 1.62 g of triethylamine are added, followed by a suspension of2.2 g of the compound obtained in Preparation 1.1 in 2 ml of THF, andthis mixture is stirred for 6 hours at RT. 3×0.8 g of triethylamine arethen added over a period of 24 hours with stirring. At the end of thereaction, the formation of an abundant precipitate is observed. Theprecipitate formed is spin-filtered off and taken up in a mixtureconsisting of 5% K₂CO₃ solution and 100 ml of EtOAc containing 10 ml ofMeOH, the organic phase is washed with 5% K₂CO₃ solution, with saturatedNaCl solution and dried over Na₂SO₄, and the solvents are partiallyevaporated off under vacuum. The precipitate formed is spin-filtered offto give 0.875 g of isomer A. The spin-filtration mother liquors arecombined and chromatographed on alumina, eluting with a gradient of aDCM/MeOH mixture of from (96/4; v/v) to (95/5; v/v). The two isomers areseparated:

[0472] the less polar, isomer A: compound of Preparation 3.1, giving anadditional 0.359 g; m.p.=265-268° C.

[0473] α_(D) ²⁵=+180° (c=0.16; chloroform);

[0474] the more polar, isomer B: compound of Preparation 3.2, which isrecrystallized from a DCM/iso-ether mixture to give 0.72 g, containing0.15 mol of iso-ether.

[0475] α_(D) ²⁵=−193.7° C. (c=0.16; chloroform).

[0476] Preparations 3.3 and 3.4

[0477](2S,4R)-1-[5-Chloro-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0478] (II): R₁=Cl; R₂=H; R₃=Cl; R₄=H; R₅=N(CH₃)₂; R₆=H

[0479] 0.8 g of the compound obtained in Preparation 2.1 a) and then 3.5ml of DIPEA are added, at RT, to a mixture of 3 g of the compoundobtained in Preparation 1.2 in 50 ml of DCM, and this mixture is stirredfor 12 hours at RT. The reaction mixture is concentrated under vacuum,the residue is extracted with EtOAc, the organic phase is washed with 5%K₂CO₃ solution, three times with water, with saturated NaCl solution anddried over Na₂SO₄, and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica gel, eluting with a DCM/MeOHmixture (95/5; v/v). The two isomers are separated:

[0480] the less polar, isomer A: compound of Preparation 3.3, which isre-chromatographed on alumina, eluting with a DCM/MeOH mixture (95/5;v/v) to give 0.182 g.

[0481] α_(D) ²⁵=+235.30 (c=0.15; chloroform);

[0482] the more polar, isomer B: compound of Preparation 3.4, which isre-chromatographed on alumina, eluting with a DCM/MeOH mixture (95/5;v/v). 0.68 g is obtained after crystallization from a DCM/iso-ethermixture; m.p.=266-267° C.

[0483] α_(D) ²⁵=−225.60 (c=0.117; chloroform).

[0484] Preparations 3.5 and 3.6

[0485](2S,4R)-1-[5-Methyl-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0486] (II): R₁=CH₃; R₂=H; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=H

[0487] 3.5 ml of DIPEA and then 1 g of the compound obtained inPreparation 2.1 a) are added to a mixture of 1.5 g of the compoundobtained in Preparation 1.3 in 15 ml of DCM and 3 ml of THF, and thismixture is stirred for 5 hours at RT. The reaction mixture isconcentrated under vacuum, the residue is extracted with EtOAc, theorganic phase is washed with 5% K₂CO₃ solution, three times with water,with saturated NaCl solution and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on silicagel, eluting with a DCM/MeOH mixture (96/4; v/v). The two isomers areseparated:

[0488] the less polar, isomer A: compound of Preparation 3.5, which iscrystallized from a DCM/iso-ether mixture. 0.183 g is obtained;m.p.=257-258° C.

[0489] α_(D) ²⁵=+151.60 (c=0.122; chloroform);

[0490] the more polar, isomer B: compound of Preparation 3.6, which isre-chromatographed on alumina, eluting with a DCM/MeOH mixture (97/3;v/v). 0.498 g is obtained, which is used without further purification.

[0491] Preparations 3.7 and 3.8

[0492](2S,4R)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(azetidin-1-ylcarbonyl)-4-hydroxypyrrolidine,isomer A and isomer B

[0493] (II):R₁ 32 Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=

[0494] R₆=H.

[0495] 1.82 g of the compound obtained in Preparation 1.1 and then 2 mlof DIPEA are added, at RT, to a solution of 0.9 g of the compoundobtained in Preparation 2.2 in 15 ml of DCM, and this mixture is heatedat 40° C. for 3 hours. The reaction mixture is concentrated undervacuum, the residue is taken up in 5% K₂CO₃ solution and extracted threetimes with EtOAc, the combined organic phases are washed with water,with saturated NaCl solution and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on alumina,eluting with a DCM/MeOH mixture (96/4; v/v). The two isomers areseparated:

[0496] the less polar, isomer A: compound of Preparation 3.7, which isrecrystallized from iso-ether to give 0.243 g; m.p.=270-271° C.

[0497] α_(D) ²⁵=+169.5° (c=0.115; chloroform);

[0498] the more polar, isomer B: compound of Preparation 3.8, to give0.716 g which is used without further purification.

[0499] Preparations 3.9 and 3.10

[0500](2S,4R)-1-[3-(2-Methoxyphenyl)-5-trifluoromethoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0501] (II): R₁=OCF₃; R₂=H; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=H

[0502] 4 ml of DIPEA and then 1.26 g of the compound obtained inPreparation 2.1 a) are added to the solution of the compound obtained inPreparation 1.4 in DCM, and this mixture is stirred for 4 hours at RT.The reaction mixture is concentrated under vacuum, the residue isextracted with EtOAc, the organic phase is washed with 5% K₂CO₃solution, twice with water, with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on alumina, eluting with DCM and then with a gradient ofa DCM/MeOH mixture up to (95.5/4.5; v/v). The two isomers are separated:

[0503] the less polar, isomer A: compound of Preparation 3.9, which iscrystallized from iso-ether to give 0.09 g; m.p.=231-233° C.

[0504] α_(D) ²⁵=+152° (c=0.123; chloroform);

[0505] the more polar, isomer B: compound of Preparation 3.10, to give0.323 g; m.p.=219-220° C.

[0506] α_(D) ²⁵=−220° (c=0.11; chloroform).

[0507] Preparations 3.11 and 3.12

[0508](2S,4R)-1-[5-Chloro-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0509] (II): R₁=Cl; R₂=6-CH₃; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=H

[0510] The solution of the compound obtained in Preparation 1.5 in DCMis cooled to 0° C., 2.25 ml of DIPEA are added, followed by 0.83 g ofthe compound obtained in Preparation 2.1 a), and this mixture is stirredfor 12 hours while allowing the temperature to return to RT. Thereaction mixture is concentrated under vacuum, the residue is extractedwith EtOAc, the organic phase is washed with 5% K₂CO₃ solution, withwater, with saturated NaCl solution and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/MeOH mixture (95/5; v/v). The twoisomers are separated:

[0511] the less polar, isomer A: compound of Preparation 3.11, which iscrystallized from iso-ether to give 0.139 g, m.p.=260-261° C.

[0512] α_(D) ²⁵=+162.50 (c=0.144; chloroform);

[0513] the more polar, isomer B: compound of Preparation 3.12, to give0.606 g which is used without further purification.

[0514] Preparations 3.13 and 3.14

[0515](2S,4R)-1-[3-(2-Chlorophenyl)-5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0516] (II): R₁=CH₃; R₂=6-CH₃; R₃=Cl; R₄=H; R₅=N(CH₃)₂; R₆=H

[0517] The solution of the compound obtained in Preparation 1.6 in DCMis cooled to 0° C., 0.6 ml of DIPEA is added, followed by 0.7 g of thecompound obtained in Preparation 2.1 a) and this mixture is stirredovernight while allowing the temperature to rise to RT. The reactionmixture is concentrated under vacuum, the residue is taken up in 5%K₂CO₃ solution and extracted with EtOAc, the organic phase is dried overNa₂SO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/MeOH mixture (95/5;v/v). The two isomers are separated:

[0518] the less polar, isomer A: compound of Preparation 3.13.

[0519] the more polar, isomer B: compound of Preparation 3.14, to give0.363 g in the form of an oil which is used without furtherpurification.

[0520] Preparations 3.15 and 3.16

[0521](2S,4R)-1-[5-Chloro-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0522] (II): R₁=Cl; R₂=H; R₃=OCH₃; R₄=3-OCH₃; R₅=N(CH₃)₂; R₆=CH₃

[0523] 1.71 ml of DIPEA and then 0.75 g of the compound obtained inPreparation 2.3 are added, at RT, to a solution of 1.1 g of the compoundobtained in Preparation 1.7 in 20 ml of DCM, and this mixture is stirredfor 3 hours at RT. The reaction mixture is concentrated under vacuum,the residue is extracted with EtOAc, the organic phase is washed with 5%K₂CO3 solution, twice with water, with saturated NaCl solution and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. The residueis chromatographed on alumina, eluting with a gradient of a DCM/MeOHmixture of from (98.5/1.5; v/v) to (98/2; v/v). The two isomers areseparated:

[0524] the less polar, isomer A: compound of Preparation 3.15, to give0.32 g

[0525] the more polar, isomer B: compound of Preparation 3.16, which isrecrystallized from iso-ether to give 0.49 g; m.p.=235-237° C.

[0526] α_(D) ²⁵=−160.7° (c=0.102; chloroform).

[0527] Preparations 3.17 and 3.18

[0528](2S,4R)-1-[5-Chloro-3-(2-methoxyphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0529] (II) R₁=Cl; R₂=6-CF₃; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=CH₃

[0530] 2.5 ml of DIPEA and 0.870 g of the compound obtained inPreparation 2.3 are added to the solution of the compound obtained inPreparation 1.8 in 10 ml of DCM, and the mixture is stirred for 10 hoursat RT. The reaction mixture is concentrated under vacuum, the residue isextracted with EtOAc, the organic phase is washed with 5% K₂CO₃solution, twice with water, with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on alumina, eluting with a gradient of a DCM/MeOHmixture (98.5/1.5; v/v). The two isomers are separated:

[0531] the less polar, isomer A: compound of Preparation 3.17, which iscrystallized from DCM to give 0.23 g; m.p.=291-293° C.

[0532] α_(D) ²⁵=+131.6° (c=0.12; chloroform);

[0533] the more polar, isomer B: compound of Preparation 3.18, which isprecipitated from hexane to give 0.44 g; m.p.=138-140° C.

[0534] α_(D) ²⁵25=157.1° (c=0.098; chloroform).

[0535] Preparations 3.19 and 3.20

[0536](2S,4R)-1-[5-Chloro-3-(2-chlorophenyl)-6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0537] (II) R₁=Cl; R₂=6-OCH₃; R₃=Cl; R₄=H; R₅=N(CH₃)₂; R₆=CH₃

[0538] 1.5 g of the compound obtained in Preparation 2.3 are added,under an argon atmosphere, to the suspension of the compound obtained inPreparation 1.9 in DCM, followed by dropwise addition of a solution of1.8 g of DIPEA in 2 ml of DCM, and the mixture is stirred for 2 hours atRT. The reaction mixture is concentrated under vacuum, the residue istaken up in 5% K₂CO₃ solution and extracted with EtOAc, the organicphase is washed with water, with saturated NaCl solution and dried overNa₂SO₄, the EtOAc is partially concentrated and the precipitate formedis left to crystallize and is spin-filtered off. An isomer is separatedout:

[0539] isomer A: compound of Preparation 3.19, to give 0.581 g;m.p.=249-250° C.

[0540] α_(D) ²⁵=+202.5° (c=0.12; chloroform).

[0541] The spin-filtration liquors are chromatographed on alumina,eluting with a DCM/MeOH mixture (98/2; v/v). The other isomer isseparated out:

[0542] the more polar, isomer B: compound of Preparation 3.20, to give0.519 g after crystallization from a DCM/EtOAc mixture; m.p.=243-244° C.

[0543] α_(D) ²⁵=−221.8° (c=0.13; chloroform).

[0544] Preparations 3.21 and 3.22

[0545](2S,4R)-1-[6-Chloro-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0546] (II): R₁=CH₃; R₂=6-Cl; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=CH₃

[0547] 5.5 ml of DIPEA and then 1.85 g of the compound obtained inPreparation 2.3 are added to the solution of the compound obtained inPreparation 1.10 in DCM, and the mixture is stirred for 12 hours at RT.The reaction mixture is concentrated under vacuum, the residue isextracted with EtOAc, the organic phase is washed with 5% K₂CO₃solution, twice with water, with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on alumina, eluting with a DCM/MeOH mixture of from(99/1; v/v) to (98/2; v/v). The two isomers are separated:

[0548] the less polar, isomer A: compound of Preparation 3.21, to give0.7 g after crystallization from iso-ether; m.p.=264° C.

[0549] α_(D) ²⁵=+183° (c=0.1; chloroform);

[0550] the more polar, isomer B: compound of Preparation 3.22, to give1.275 g after crystallization from iso-ether; m.p.=245° C.

[0551] α_(D) ²⁵=−195.1° (c=0.12; chloroform).

[0552] Preparations 3.23 and 3.24

[0553](2S,4R)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-ethoxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0554] (II): R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=—CH₂CH₃

[0555] A mixture of 2.15 g of the compound obtained in Preparation 1.1,2 g of the compound obtained in Preparation 2.4 and 1.4 g oftriethylamine in 50 ml of THF is stirred for 48 hours at RT. Thereaction mixture is concentrated under vacuum, the residue is taken upin water and extracted with DCM, the organic phase is dried over Na₂SO₄and the solvent is evaporated off under vacuum. The residue is taken upin a DCM/EtOAc mixture (50/50; v/v), heated to reflux and left to stand.The precipitate formed is spin-filtered off and isolated:

[0556] isomer A: compound of Preparation 3.23, to give 1.1 g; m.p.=236°C.

[0557] α_(D) ²⁵=+109° (c=0.22; chloroform).

[0558] The spin-filtration liquors are chromatographed on silica gel,eluting with an EtOAc/MeOH mixture (97/3; v/v) and the other isomer isseparated out:

[0559] the more polar, isomer B: compound of Preparation 3.24, to give 1g

[0560] α_(D) ²⁵=−164° (c=0.25; chloroform).

[0561] Preparations 3.25 and 3.26

[0562](2S,4R)-1-[5-Chloro-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0563] (II) R₁=Cl; R₂=H; R₃=OCH₃; R₄=3-OCH₃; R₅=N(CH₃)₂; R₆=H

[0564] 2.5 ml of DIPEA and then 1 g of the compound obtained inPreparation 2.1 a) are added, at RT, to a solution of 1.6 g of thecompound obtained in Preparation 1.7 in 10 ml of DCM and the mixture isstirred for 48 hours at RT. The precipitate formed, corresponding toisomer A below, is spin-filtered off. The filtrate is concentrated undervacuum, the residue is extracted with EtOAc, the organic phase is washedwith 5% K₂CO₃ solution, with water, with saturated NaCl solution anddried over Na₂SO₄, and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica gel, eluting with a gradient of aDCM/MeOH mixture of from (99/1; v/v) to (93/7; v/v). The two isomers areseparated:

[0565] the less polar, isomer A: compound of Preparation 3.25, which isrecrystallized with the first crop above from a DCM/iso-ether mixture;m.p.=261-263° C.

[0566] α_(D) ²⁵=+119.3° (c=0.135; chloroform)

[0567] the more polar, isomer B: compound of Preparation 3.26, which isrecrystallized in a DCM/iso-ether mixture to give 0.94 g; m.p.=167-169°C.

[0568] α_(D) ²⁵=−168.6° (c=0.172; chloroform).

[0569] Preparations 3.27 and 3.28

[0570](2S,4R)-1-[5,6-Dichloro-3-(2-chlorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0571] (II): R₁=Cl; R₂=6-Cl; R₃=Cl; R₄=H; R₅=N(CH₃)₂; R₆=H

[0572] 1.6 g of the compound obtained in Preparation 1.11 and then 2.13ml of DIPEA are added, at RT, to a mixture of 0.8 g of the compoundobtained in Preparation 2.1 a) in 15 ml of DCM, and the mixture isstirred for 15 minutes at RT. The reaction mixture is concentrated undervacuum, the residue is extracted with EtOAc, the organic phase is washedwith 5% K₂CO3 solution, with water, with saturated NaCl solution anddried over Na₂SO₄, and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica gel, eluting with a DCM/MeOHmixture (95/5; v/v). The two isomers are separated:

[0573] the less polar, isomer A: compound of Preparation 3.27, which iscrystallized from iso-ether to give 0.08 g; m.p. >260° C.

[0574] α_(D) ²⁵=+219.4° (c=0.103; chloroform)

[0575] the more polar, isomer B: compound of Preparation 3.28, to give0.661 g which is used without further purification.

[0576] Preparations 3.29 and 3.30

[0577] Methyl(2S,4R)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-2-pyrrolidinecarboxylate,Isomer A and Isomer B

[0578] (II): R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=OCH₃; R₆=H

[0579] 4 ml of DIPEA and then 1.64 g of methyl(2S,4R)-4-hydroxy-2-pyrrolidinecarboxylate hydrochloride are added, atRT, to a mixture of 1.4 g of the compound obtained in Preparation 1.1 in20 ml of DCM, and the mixture is stirred for 12 hours at RT. Thereaction mixture is concentrated under vacuum, the residue is extractedwith EtOAc, the organic phase is washed with 5% K₂CO₃ solution, withwater, with saturated NaCl solution and dried over sodium sulphate, andthe solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/MeOH mixture (97/3;v/v). The two isomers are separated:

[0580] the less polar isomer, isomer A: compound of Preparation 3.29, togive 0.3 g; m.p.=234-235° C.

[0581] α_(D) ²⁵=+143.3° (c=0.136; chloroform);

[0582] the more polar isomer, isomer B: compound of Preparation 3.30,which is recrystallized from a DCM/iso-ether/hexane mixture to give 1.1g

[0583] α_(D) ²⁵=199.1° (c=0.112; chloroform).

[0584] Preparation 3.31

[0585] Methyl(2S,4R)-1-[5-chloro-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-2-pyrrolidinecarboxylate,mixture of the two diastereoisomers

[0586] (II): R₁=Cl; R₂=6-CH₃; R₃=OCH₃; R₄=H; R₅=OCH₃; R₆=H

[0587] The solution of the compound obtained in Preparation 1.5 in DCMis concentrated under vacuum, the residue is taken up in a mixture of 20ml of THF and 10 ml of DCM, 0.715 g of methyl(2S,4R)-4-hydroxy-2-pyrrolidinecarboxylate hydrochloride is added, atRT, followed by 0.8 g of triethylamine, and the mixture is stirred for48 hours at RT. The reaction mixture is concentrated under vacuum, theresidue is extracted with DCM, the organic phase is washed with waterand dried over Na₂SO₄, and the solvent is evaporated off under vacuum.The residue is chromatographed on silica gel, eluting with a DCM/EtOAcmixture (50/50; v/v). 1.8 g of a mixture of the two diastereoisomers areobtained.

[0588] Preparation 3.32

[0589](2S,4S)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,mixture of the two diastereoisomers

[0590] (II): R₁ Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=H

[0591] A mixture of 4.6 g of the compound obtained in Preparation 2.5 in50 ml of DCM is cooled to 4° C., 2.7 g of the compound obtained inPreparation 1.1 and then 5 ml of triethylamine are added and the mixtureis stirred for 48 hours at RT. The reaction mixture is concentratedunder vacuum, the residue is extracted with EtOAc, the organic phase iswashed with 5% Na₂CO₃ solution, with saturated NaCl solution and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. The residueis chromatographed on alumina, eluting with a DCM/MeOH mixture (98/2;v/v). 1.6 g of a mixture of the two diastereoisomers are obtained.

[0592] Preparation 3.33

[0593](2S,4R)-1-[5-Chloro-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer

[0594] (II): R₁=Cl; R₂=H; R₃=OCH₂CH₃; R₄=H; R₅=N(CH₃)₂; R₆=H

[0595] 1.38 g of the compound obtained in Preparation 2.1 a) and then1.46 g of DIPEA are added to a solution of 2 g of the compound obtainedin Preparation 1.12 in 20 ml of DCM, and the mixture is stirred for 12hours at RT. The reaction mixture is concentrated under vacuum, theresidue is extracted with EtOAc, the organic phase is washed with 5%K₂CO₃ solution and dried over Na₂SO₄, and the solvent is evaporated offunder vacuum. The residue is chromatographed on alumina, eluting with aDCM/MeOH mixture (95/5; v/v). The two diastereoisomers are separated andthe more polar compound is collected and re-chromatographed on silicagel, eluting with a DCM/EtOAc mixture (60/40; v/v) and then withDCM/MeOH (94/6; v/v). 0.726 g of the expected product is obtained.

[0596] Preparations 3.34 and 3.35

[0597](2S,4R)-1-[5-Chloro-3-(2-trifluoromethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0598] (II): R₁=Cl; R₂=H; R₃=OCF₃; R₄=H; R₅=N(CH₃)₂; R₆=H

[0599] A mixture of 1.6 g of the compound obtained in Preparation 1.13,0.8 g of the compound obtained in Preparation 2.1 a) and 1 ml of DIPEAin 20 ml of DCM is stirred for 24 hours at RT. The precipitate formed,corresponding to isomer A, which is the less polar compound on silicagel, DCM/MeOH (98/2; v/v) (compound of Preparation 3.34), isspin-filtered off. The spin-filtration liquors are placed at 0° C. for48 hours and the precipitate formed, again corresponding to isomer A, isspin-filtered off. The spin-filtration liquors are washed with water,the organic phase is dried over Na₂SO₄ and the solvent is evaporated offunder vacuum. The residue is chromatographed on silica gel, eluting witha DCM/MeOH mixture (98/2; v/v). The other isomer is separated out:

[0600] the more polar, isomer B: compound of Preparation 3.35, to give0.2 g.

[0601] Preparations 3.36 and 3.37

[0602](2S,4R)-1-[5-Chloro-3-(2,3-difluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0603] (II): R₁=Cl; R₂=H; R₃=F; R₄=3-F; R₅=N(CH₃)₂; R₆=H

[0604] A mixture of 0.4 g of the compound obtained in Preparation 1.14,0.3 g of the compound obtained in Preparation 2.1 a) and 0.45 g of DIPEAin 20 ml of DCM is stirred for 2 hours at RT. The precipitate formed,corresponding to isomer A, which is the less polar compound on alumina,DCM/MeOH (98/2; v/v) (compound of Preparation 3.36), is spin-filteredoff. The spin-filtration liquors are concentrated under vacuum, theresidue is taken up in an EtOAc/acetone mixture, the resulting mixtureis left for 12 hours under cold conditions, and the precipitate, againcorresponding to isomer A, is spin-filtered off. The spin-filtrationliquors are washed with water, the organic phase is dried over Na₂SO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on alumina, eluting with a DCM/MeOH mixture (98/2; v/v).The other isomer is separated out:

[0605] the more polar, isomer B: compound of Preparation 3.37, to give0.1 g.

[0606] α_(D) ²⁵=−231° (c=0.16; chloroform).

[0607] Preparations 3.38 and 3.39

[0608](2S,4R)-1-[5-Chloro-3-(2,4-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0609] (II): R₁=Cl; R₂=H; R₃=OCH₃; R₄=4-OCH₃; R₅=N(CH₃)₂; R₆=H

[0610] 1.5 g of the compound obtained in Preparation 2.1 a) are added toa solution of the compound obtained in Preparation 1.15 and 1 ml oftriethylamine in 20 ml of DCM, and this mixture is stirred for 1 hour atRT. The reaction mixture is washed twice with water, the organic phaseis dried over Na₂SO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on alumina, eluting with DCM and then with aDCM/MeOH mixture (98.2; v/v). The two isomers are separated:

[0611] the less polar, isomer A: compound of Preparation 3.38

[0612] the more polar, isomer B: compound of Preparation 3.39, to give0.26 g

[0613] α_(D) ²⁵=−157° (c=0.15; chloroform).

[0614] Preparation 3.40

[0615](2S,4R)-1-[5-Chloro-3-(1,3-benzodioxol-4-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Laevorotatory Isomer

[0616] (II): R₁=Cl; R₂=H; R₃+R₄=2,3-O—CH₂—O—; R₅=N(CH₃)₂; R₆=H

[0617] A mixture of 1.7 g of the compound obtained in Preparation 1.16,0.9 g of the compound obtained in Preparation 2.1 a) and 1 ml of DIPEAin 20 ml of DCM is stirred for 2 hours at RT. The reaction mixture iswashed with water, the organic phase is dried over Na₂SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon alumina, eluting with a DCM/MeOH mixture (97/3; v/v). The twodiastereoisomers are separated out and the more polar compound iscollected. 0.42 g of the expected product is obtained.

[0618] α_(D) ²⁵=−108° (c=0.12; chloroform).

[0619] Preparations 3.41 and 3.42

[0620](2S,4R)-1-[5,6-Dichloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Isomer A and Isomer B

[0621] (II): R₁=Cl; R₂=6-Cl; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=H

[0622] A mixture of 1.57 g of the compound obtained in Preparation 1.17,1.45 g of the compound obtained in Preparation 2.1 a) and 0.8 ml ofDIPEA in 15 ml of DCM is stirred for 1 hour 30 minutes at RT. Theprecipitate formed, corresponding to isomer A, which is the less polarcompound on silica gel, DCM/MeOH (94/6; v/v), is spin-filtered off. Thespin-filtration liquors are concentrated under vacuum, the residue isextracted with EtOAc, the organic phase is washed with 5% K₂CO₃solution, with water, with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with the DCM/MeOH mixture (94/6;v/v). The two isomers are separated:

[0623] the less polar, isomer A: compound of Preparation 3.41, which iscrystallized from an iso-ether/MeOH mixture to give 0.295 g;m.p.=261-262° C.

[0624] α_(D) ²⁵=+113.8° (c=0.12; chloroform)

[0625] the more polar, isomer B: compound of Preparation 3.42, to give0.74 g.

[0626] Preparations 3.43 and 3.44

[0627] Tert-Butyl2-[[(3R,5S)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl)-3-pyrrolidinyl]oxy]acetate,Isomer A and Isomer B

[0628] (II): R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=—CH₂COOC(CH₃)₃

[0629] 200 ml of THF, 1.87 g of triethylamine and then 4.5 g of thecompound obtained in Preparation 1.1 are added to the solution of thecompound obtained in Preparation 2.6 and the mixture is refluxed for 48hours. The product is concentrated under vacuum and the residue ischromatographed on silica gel, eluting with a DCM/MeOH mixture (96/4;v/v). The isomers are separated:

[0630] the less polar, isomer A: compound of Preparation 3.43, to give 1g

[0631] the more polar, isomer B: compound of Preparation 3.44, to give 3g in the form of an oil.

[0632] α_(D) ²⁵=−154° (c=0.37; chloroform).

[0633] Preparation 3.45

[0634](3R,5S)-1-[5-Chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)-carbonyl]-3-pyrrolidinyl3-(4-morpholinyl)propanoate, mixture of the two diastereoisomers

[0635] (II): R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=−N(CH₃)₂; R₆=−CO−CH₂CH₂

[0636] A solution of 3 g of the compound obtained in Preparation 1.1 in100 ml of THF is added to the solution of the compound obtained inPreparation 2.7 in EtOAc, and the mixture is stirred for 4 days at RT.The reaction mixture is concentrated under vacuum, the residue isextracted with EtOAc, the organic phase is washed with water and driedover Na₂SO₄, and the solvent is evaporated off under vacuum. The residueis chromatographed on silica gel, eluting with a DCM/MeOH mixture (92/8;v/v). 4.2 g of the expected product are obtained in the form of a foam.

EXAMPLE 1

[0637](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide,laevorotatory isomer, 0.25 iso-ether

[0638] (I): R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=H; R₇=2-OCH₃;R₈=OCH₃

[0639] A mixture of 0.67 g of the compound obtained in Preparation 3.2(isomer B) in 10 ml of DMF is cooled to 0° C., under an argonatmosphere, 0.069 g of 60% sodium hydride in oil is added and themixture is stirred until the evolution of gas has ceased. 0.404 g of2,4-dimethoxybenzenesulphonyl chloride is then added and the mixture isstirred for 3 hours at RT. The reaction mixture is poured into 5% K₂CO₃solution and extracted with EtOAc, the organic phase is washed withwater, with saturated NaCl solution and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. The residue is chromatographedon alumina, eluting with a DCM/MeOH mixture (99/1; v/v). 0.565 g of theexpected product is obtained after crystallization from a DCM/iso-ethermixture.

[0640] α_(D) ²⁵=−200° C. (c=0.26; chloroform).

[0641]¹H NMR: DMSO-d₆+TFA, 360 K: δ (ppm): 1.6: mt: 2H; 2.1 to 3.1: m:8H; 3.35: s: 3H; 3.7: s: 3H; 3.9: s: 3H; 4.4: mt: 1H; 4.6: mt: 1H; 6.6to 8.1: m: 10H.

EXAMPLE 2

[0642](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidine-carboxamide,Laevorotatory Isomer

[0643] (I): R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=H; R₇=2-OCH₃;R₈=OCH₃

[0644] 0.04 g of 60% sodium hydride in oil is added, at RT and under anargon atmosphere, to a solution of 0.559 g of the compound obtained inExample 1 in 6 ml of DMF, and stirring is continued until the evolutionof gas has ceased. 0.11 ml of methyl iodide is then added and themixture is stirred for 24 hours at RT. A further 0.04 g of 60% sodiumhydride in oil is added, followed by 0.33 ml of methyl iodide, withstirring for 3 days at RT. The reaction mixture is poured into water andextracted with EtOAc, the organic phase is washed with water, withsaturated NaCl solution and dried over Na₂SO₄, and the solvent isevaporated off under vacuum. The residue is chromatographed on silicagel, eluting with a DCM/MeOH mixture (98/2; v/v). 0.082 g of theexpected product is obtained after crystallization from a DCM/iso-ethermixture; m.p.=189-191° C.

EXAMPLE 3

[0645](2S,4R)-1-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide,Laevorotatory Isomer

[0646] (I): R₁=Cl; R₂=H; R₃=Cl; R₄=H; R₅=N(CH₃)₂; R₆=H; R₇=2-OCH₃;R₈=OCH₃

[0647] A mixture of 0.567 g of the compound obtained in Preparation 3.4(isomer B) in 5.5 ml of DMF is cooled to 0° C., under an argonatmosphere, 0.062 g of 60% sodium hydride in oil is added and themixture is stirred for 10 minutes. 0.338 g of2,4-dimethoxybenzenesulphonyl chloride is then added and the mixture isstirred for 3 hours at RT. Water is added to the reaction mixture, theresulting mixture is extracted three times with EtOAc, the combinedorganic phases are washed with saturated NaCl solution and dried overNa₂SO₄, and the solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/MeOH mixture (98/2;v/v). 0.647 g of the expected product is obtained after crystallizationfrom iso-ether; m.p.=254-256° C.

[0648] α_(D) ²⁵=−250° (c=0.142; chloroform).

EXAMPLE 4

[0649](2S,4R)-1-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer

[0650] (I): R₁=Cl; R₂=6-OCH₃; R₃=Cl; R₄=H; R₅=N(CH₃)₂; R₆=H; R₇=2-OCH₃;R₈=OCH₃

[0651] 0.072 g of 60% sodium hydride in oil is added at RT, under anargon atmosphere, to a suspension of 0.719 g of the compound obtained inPreparation 3.20 (isomer B) in 7 ml of DMF, and the mixture is stirreduntil the evolution of gas has ceased. 0.390 g of2,4-dimethoxybenzenesulphonyl chloride is then added and the mixture isstirred for 3 hours at RT. The reaction mixture is poured into 5% K₂CO₃solution and extracted with EtOAc and then with DCM, the organic phasesare washed separately with water, dried over Na₂SO₄ and combined, andthe solvents are partially concentrated under vacuum to the point ofcrystallization. The precipitate formed is spin-filtered off to give0.735 g of the expected product; m.p.=283-288° C.

[0652] α_(D) ²⁵=266.3° (c=0.11; chloroform).

EXAMPLE 5

[0653](2S,4R)-1-[5-Chloro-1-[(3,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide,Laevorotatory Isomer

[0654] (I): R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=H; R₇=2-OCH₃;R₈=OCH₃

[0655] A solution of 0.043 g of the compound obtained in Preparation 3.2(isomer B) in 1 ml of THF is cooled to −30° C., under a nitrogenatmosphere, a solution of 0.22 g of potassium tert-butoxide in 1 ml ofTHF is added and the mixture is stirred for 15 minutes while allowingthe temperature to rise to 0° C. A solution of 0.035 g of3,4-dimethoxybenzene-sulphonyl chloride in 1 ml of THF is then addedwith stirring, while allowing the temperature to return to RT, and themixture is then heated at 30° C. for 2 hours 15 minutes. 0.1 g ofPS-Trisamine is added and the mixture is stirred for 1 hour 15 minutesat RT. 1 ml of DCM and 1 ml of water are added with stirring, theaqueous phase is then removed by filtration through a Whatman FT 5.0μPTFE filter and the organic phase is concentrated under vacuum. Theresidue is chromatographed on silica gel, eluting with DCM and then witha DCM/EtOAc mixture of from (90/10; v/v) to (70/30; v/v) and finallywith a DCM/MeOH mixture of from (99/1; v/v) to (96/4; v/v). 0.026 g ofthe expected product is obtained.

[0656] MH⁺=629.

EXAMPLE 6

[0657] Methyl(2S,4R)-1-[5-chloro-3-(2-methoxyphenyl)-1-[(3,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-2-pyrrolidinecarboxylate,laevorotatory isomer

[0658] (I): R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=OCH₃; R₆=H; R₇=3-OCH₃;R₈=OCH₃

[0659] A mixture of 0.477 g of the compound obtained in Preparation 3.30(isomer B) in 4.7 ml of DMF is cooled to 0° C. under an argonatmosphere, 0.055 g of 60% sodium hydride in oil is added and themixture is stirred for 10 minutes. 0.297 g of3,4-dimethoxy-benzenesulphonyl chloride is then added, and the mixtureis stirred for 3 hours 30 minutes at RT. Water is added to the reactionmixture, the resulting mixture is extracted three times with EtOAc, thecombined organic phases are washed with water, with saturated NaClsolution and dried over Na₂SO₄, and the solvent is evaporated off undervacuum. The residue is chromatographed on silica gel, eluting with aDCM/MeOH mixture (97/3; v/v). 0.3 g of the expected product is obtainedafter crystallization from a DCM/iso-ether mixture.

[0660] α_(D) ²⁵=−139.1° (c=0.115; chloroform).

EXAMPLES 7 AND 8

[0661](2S,4S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide,Laevorotatory Isomer and Dextrorotatory Isomer

[0662] (I): R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=H; R₇=2-OCH₃;R₈=OCH₃

[0663] A mixture of 0.82 g of the compound obtained in Preparation 3.32(mixture of diastereoisomers) in 5 ml of DMF is cooled to 4° C., under anitrogen atmosphere, 0.076 g of 60% sodium hydride in oil is added andthe mixture is stirred at 4° C. for 30 minutes. 0.451 g of2,4-dimethoxybenzenesulphonyl chloride is then added and the mixture isstirred for 3 hours at RT. 50 ml of water are added to the reactionmixture, the resulting mixture is extracted with EtOAc, the organicphase is washed with 5% Na₂CO₃ solution, with saturated NaCl solutionand dried over Na₂SO₄, and the solvent is evaporated off under vacuum.The residue is chromatographed on alumina, eluting with a DCM/MeOHmixture (99.2/0.8; v/v). The two diastereoisomers are separated:

[0664] the less polar: compound of Example 7, 0.122 g of which iscollected after crystallization from hexane; m.p=151° C.

[0665] α_(D) ²⁵=−154° (c=0.1; chloroform)

[0666] the more polar, compound of Example 8, which is obtained aftercrystallization from a DCM/iso-ether mixture; m.p.=283° C.

[0667] α_(D) ²⁵=+140° (c=0.1; chloroform)

[0668] Working according to the procedures described in the Examplesabove, starting with the compounds of formula (II) described inPreparations 3 and 2,4-dimethoxybenzenesulphonyl chloride, the compoundsaccording to the invention collated in Table I below are prepared: TABLEI (I)

Solvate, hydrate; m.p.° C.; crystallization Ex- solvent; α_(D) ²⁵ amplesR1 R2 R3 R4 R5 R6 (chloroform) 9 CH₃ H OCH₃ H —N(CH₃)₂ H 0.65 H₂O (a)162-164 iso-ether −202.8° (c = 0.139) 10 (b) Cl H OCH₃ H

H 0.25 H₂O 161-162 iso-ether −205.9° (c = 0.135) 11 OCF₃ H OCH₃ H—N(CH₃)₂ H — (c) 147 DCM/hexane −223° (c = 0.13) 12 Cl 6-CH₃ OCH₃ H—N(CH₃)₂ H — (d) — iso-ether −162.1° (c = 0.103) 13 CH₃ 6-CH₃ Cl H—N(CH₃)₂ H 1 H₂O (e) 232 DCM/iso-ether −239° (c = 0.1) 14 Cl H OCH₃3-OCH₃ —N(CH₃)₂ —CH₃ — (f) 233-234 DCM/iso-ether −198° (c = 0.11) 15 Cl6-CF₃ OCH₃ H —N(CH₃)₂ —CH₃ — (g) 230-231 DCM/iso-ether −170° (c = 0.11)16 CH₃ 6-Cl OCH₃ H —N(CH₃)₂ —CH₃ — (h) 238-240 DCM/iso-ether −163.2° (c= 0.12) 17 Cl H OCH₃ H —N(CH₃)₂ —CH₂CH₃ — (i) iso-ether/hexane −207° (c= 0.2) 18 Cl H OCH₃ 3-OCH₃ —N(CH₃)₂ H — (j) 148-150 DCM/iso-ether−207.3° (c = 0.11) 19 Cl 6-Cl Cl H —N(CH₃)₂ H — (k) 181 iso-ether−265.3° (c = 0.17) 20 Cl H OCH₃ H OCH₃ H — (l) 185-186 DCM/iso-ether−180.9° (c = 0.15) 21 Cl 6-CH₃ OCH₃ H OCH₃ H — (m) 226 DCM/iso-ether−131° (c = 0.17) 22 Cl H OCH₂ H —N(CH₃)₂ H — (n) CH₃ 135-149ether/iso-ether −188.3° (c = 0.11) 23 Cl H OCF₃ H —N(CH₃)₂ H — (o) — —−105° (c = 0.12) 24 Cl H F 3-F —N(CH₃)₂ H — (p) — — −174° (c = 0.15) 25Cl H OCH₃ 4-OCH₃ —N(CH₃)₂ H — (q) 183 iso-ether −194° (c = 0.16) 26 Cl H2,3-O—CH₂—O— —N(CH₃)₂ H — (r) 192 iso-ether −200° (c = 0.16) 27 Cl 6-ClOCH₃ H —N(CH₃)₂ H — (s) 160-161 iso-ether/DCM −138.8° (c = 0.11)

EXAMPLE 28

[0669] Tert-Butyl 2-[[(3R,5S)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]acetate,Laevorotatory Isomer.

[0670] (I): R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=—CH₂COOC(CH₃)₃;R₇=2-OCH₃; R₈=OCH₃.

[0671] This compound is prepared according to the procedure described inExample 3, starting with 2.9 g of the compound obtained in Preparation3.44 (isomer B), 0.233 g of 60% sodium hydride in oil, 15 ml of DMF and1.25 g of 2,4-dimethoxybenzenesulphonyl chloride. The product ischromatographed on silica gel, eluting with a DCM/EtOAc mixture (80/20;v/v). 3 g of the expected product are obtained after crystallizationfrom hexane.

[0672] α_(D) ²⁰=−159° (c=0.23; chloroform).

EXAMPLE 29

[0673] 2-[[(3R,5S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]aceticacid 0.55 trifluoroacetate, Laevorotatory Isomer.

[0674] (I), TFA: R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=—CH₂COOH;R₇=2-OCH₃; R₈=OCH₃.

[0675] A mixture of 3 g of the compound obtained in Example 28 and 15 mlof TFA in 15 ml of DCM is stirred for 3 hours at RT. The reactionmixture is concentrated under vacuum, the residue is taken up iniso-ether and the precipitate formed is spin-filtered off. 2.2 g of theexpected product are obtained.

[0676] α_(D) ²⁰=−179° (c=0.31; chloroform).

EXAMPLE 30

[0677](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-[2-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-2-oxoethoxy]-N,N-dimethyl-2-pyrrolidinecarboxamide,laevorotatory isomer.

[0678] (I): R₁=Cl; R₂=H; R₃ OCH₃; R₄=H; R₅=N(CH₃)₂; R₆=—CH₂CONHC(CH₃)(CH₂OH)₂; R₇=2-OCH₃; R₈=OCH₃.

[0679] A mixture of 0.5 g of the compound obtained in Example 29, 0.085g of 2-amino-2-methyl-1,3-propanediol, 0.290 g of BOP and 0.187 g oftriethylamine in 20 ml of DCM is stirred for 3 hours at RT. The reactionmixture is diluted by addition of DCM, the organic phase is washed withwater, with saturated Na₂CO₃ solution and dried over Na₂SO₄, and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica gel, eluting with a DCM/MeOH mixture (94/6; v/v). 0.31 g ofthe expected product is obtained after crystallization from iso-ether;m.p.=154° C.

[0680] α_(D) ²⁰=−142 (c=0.19; chloroform).

EXAMPLE 31

[0681](2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-4-[2-oxo-2-(1-piperazinyl)ethoxy]-2-pyrrolidinecarboxamidebis(trifluoroacetate), laevorotatory isomer.

[0682] (I), 2TFA: R₁=Cl; R₂=H; R₃=OCH₃; R₄H; R₅=−N(CH₃)₂; R₆=—CH₂—CO—

[0683] ; R₇=2-OCH; R₈=OCH

[0684] A)

[0685] A mixture of 0.7 g of the compound obtained in Example 29, 0.2 gof 1-(tert-butoxycarbonyl)piperazine, 0.404 g of BOP and 0.263 g oftriethylamine in 20 ml of DCM is stirred for 2 hours at RT. Water isadded to the reaction mixture and the resulting mixture is extractedwith DCM, the organic phase is washed with saturated Na₂CO₃ solution anddried over Na₂SO₄, and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica gel, eluting with a DCM/MeOHmixture (97/3; v/v). The product thus obtained is taken up in hexane andthe precipitate formed is spin-filtered off to give 0.7 g.

[0686] B)

[0687] A mixture of 0.7 g of the compound obtained in step A and 10 mlof TFA in 10 ml of DCM is stirred for 3 hours. The reaction mixture isconcentrated under vacuum, the residue is taken up in ether and theprecipitate formed is spin-filtered off. 0.6 g of the expected productis obtained; m.p.=166° C.

[0688] α_(D) ²⁰=−133° (c=0.27; chloroform).

EXAMPLE 32

[0689](2S,4R)-1-[(2,4-Dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-4-[2-oxo-2-(4-morpholinyl)ethoxy]-2-pyrrolidinecarboxamide,laevorotatory isomer.

[0690] (I): R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=−N(CH₃)₂;

[0691] R₆=−CH₂—CO—

[0692] ; R₇=2-OCH₃; R₈=OCH₃.

[0693] A mixture of 0.6 g of the compound obtained in Example 29, 0.085g of morpholine, 0.347 g of BOP and 0.227 g of triethylamine in 20 ml ofDCM is stirred for 2 hours at RT. The reaction mixture is extracted withDCM, the organic phase is washed with water and dried over Na₂SO₄, andthe solvent is evaporated off under vacuum. The residue ischromatographed on silica gel, eluting with a DCM/MeOH mixture (95/5;v/v). 0.53 g of the expected product is obtained after crystallizationfrom iso-ether; m.p.=210° C.

[0694] α_(D) ²⁰=−153° (c=0.28; chloroform).

EXAMPLES 33 AND 34

[0695](3R,5S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl3-(4-morpholinyl)propanoate, laevorotatory isomer and dextrorotatoryisomer.

[0696] (I): R₁=Cl; R₂=H; R₃=OCH₃; R₄=H; R₅=−N(CH₃)₂;

[0697] R₆=−CO—CH₂CH₂

[0698] ; R₇=2-OCH₃; R₈=OCH₃.

[0699] These compounds are prepared according to the procedure describedin Example 3, starting with 3.1 g of the compound obtained inPreparation 3.45, 20 ml of DMF, 0.238 g of 60% sodium hydride in oil and1.27 g of 2,4-dimethoxybenzenesulphonyl chloride. The product ischromatographed on silica gel, eluting with a DCM/MeOH mixture (90/10;v/v). The two diastereoisomers are separated:

[0700] the less polar: compound of Example 33, 2.8 g of which areobtained after solidification in hexane.

[0701] α_(D) ²⁰=−154° (c=0.3; chloroform).

[0702] the more polar: compound of Example 34, 1.3 g of which areobtained after solidification in hexane.

[0703] α_(D) ²⁵=+127° (c=0.29; chloroform).

1. Compound of formula:

in which: R₁ represents a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; a trifluoromethyl radical; a trifluoromethoxy radical; R₂ represents a hydrogen atom; a halogen atom; a (C₁-C₄) alkyl; a (C₁-C₄) alkoxy; a trifluoromethyl radical; or R₂ is in position -6- of the indol-2-one ring and R₁ and R₂ together represent a divalent trimethylene radical; R₃ represents a halogen atom; a hydroxyl; a (C₁-C₂)alkyl; a (C₁-C₂)alkoxy; a trifluoromethoxy radical; R₄ represents a hydrogen atom; a halogen atom; a (C₁-C₂)alkyl; a (C₁-C₂)alkoxy; or R₄ is in position -3- of the phenyl and R₃ and R₄ together represent a methylenedioxy radical; R₅ represents an ethylamino group; a dimethylamino group; an azetidin-1-yl radical; a (C₁-C₂)alkoxy; R₆ represents a hydrogen atom; a (C₁-C₄)alkyl; a group —(CH₂)n-CO—R₉; a group —CO—(CH₂)n-NR₁₀R₁₁; R₇ represents a (C₁-C₄)alkoxy; R₈ represents a (C₁-C₄)alkoxy; R₉ represents a hydroxyl; a (C₁-C₄)alkoxy; a group —NR₁₂R₁₃; R₁₀ and R₁₁ each independently represent a (C₁-C₄) alkyl; or R₁₀ and R₁₁, together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl; R₁₂ represents a hydrogen or a (C₁-C₄)alkyl; R₁₃ represents a (C₁-C₄)alkyl; a —C(CH₃)₂CH₂OH group; a —C(CH₃)(CH₂OH)₂ group; a —C(CH₂OH)₃ group; or R₁₂ and R₁₃, together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl; n is 1 or 2; the solvates and/or hydrates thereof and the possible salts thereof with mineral or organic acids.
 2. Compound according to claim 1, in the form of optically pure isomers.
 3. Compound according to claim 2, of formula:

in which: the carbon atom bearing substituent OR₆ has the (R) configuration and the carbon atom in position 3 of the indol-2-one has either the (R) configuration or the (S) configuration.
 4. Compound according to claim 3, in the form of the laevorotatory isomer.
 5. Compound according to claim 4, of formula (Ia) in which: R₁ represents a chlorine atom, a methyl radical or a trifluoromethoxy radical; R₂ represents a hydrogen atom or is in position -6- of the indol-2-one and represents a chlorine atom, a methyl radical, a methoxy radical or a trifluoromethyl radical; R₃ represents a chlorine atom, a fluorine atom, a methoxy radical or an ethoxy radical; R₄ represents a hydrogen atom or is in position -3- or -4- of the phenyl and represents a fluorine atom or a methoxy radical; or R₄ is in position -3- of the phenyl and, together with R₃, represent a methylenedioxy radical; R₅ represents a dimethylamino radical or a methoxy radical; R₆ represents a hydrogen atom; a methyl radical; an ethyl radical; a tert-butyloxycarbonylmethyl radical; a carboxymethyl radical; a [[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]carbonylmethyl radical; a (1-piperazinyl)carbonylmethyl radical; a (4-morpholinyl)carbonylmethyl radical; a 3-(4-morpholinyl)propanoyl radical; R₇ is in position -2- of the phenyl and represents a methoxy radical; R₈ represents a methoxy radical; and the salts thereof with mineral or organic acids, and the solvates and/or hydrates thereof.
 6. Compound according to claim 5, chosen from: (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; (2S,4R)-1-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer; (2S,4R)-1-[5-Chloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-6-methoxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; (2S,4R)-1-[5-Chloro-1-[(3,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; Methyl (2S,4R)-1-[5-chloro-3-(2-methoxyphenyl)-1-[(3,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-2-pyrrolidinecarboxylate, laevorotatory isomer; (2S,4R)-1-[5-Methyl-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-2-(azetidin-1-ylcarbonyl)-4-hydroxy-pyrrolidinecarboxamide, laevorotatory isomer; (2S,4R)-1-[5-Trifluoromethoxy-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer; (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer; (2S,4R)-1-[3-(2-Chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-5,6-dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-6-trifluoromethyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer; (2S,4R)-1-[6-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer; (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-ethoxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2,3-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; (2S,4R)-1-[5,6-Dichloro-3-(2-chlorophenyl)-1-[(2,4-dimethoxyphenyl)sulphonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; Methyl(2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-2-pyrrolidinecarboxylate, laevorotatory isomer; Methyl(2S,4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-6-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-methoxy-2-pyrrolidine-carboxylate, laevorotatory isomer; (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2,3-difluorophenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2,4-dimethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(1,3-benzodioxol-4-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; (2S,4R)-1-[5,6-Dichloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidine-carboxamide, laevorotatory isomer; tert-Butyl 2-[[(3R, 5S)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]acetate, laevorotatory isomer; 2-[[(3R,5S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl]oxy]acetic acid, laevorotatory isomer; (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-[2-[[2-hydroxy-1-(hydroxymethyl)-1-methylethyl]amino]-2-oxoethoxy]-N,N-dimethyl-2-pyrrolidinecarboxamide, laevorotatory isomer; (2S,4R)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)-sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-4-[2-oxo-2-(1-piperazinyl)ethoxy]-2-pyrrolidinecarboxamide, laevorotatory isomer; (2S,4R)-1-[[(2,4-Dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethyl-4-[2-oxo-2-(4-morpholinyl)ethoxy]-2-pyrrolidinecarboxamide, laevorotatory isomer; (3R, 5S)-1-[5-Chloro-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-5-[(dimethylamino)carbonyl]-3-pyrrolidinyl 3-(4-morpholinyl)propanoate, laevorotatory isomer; as well as the possible salts thereof with mineral or organic acids, and the solvates and/or hydrates thereof.
 7. Process for preparing compounds of formula (I) according to claim 1, possible salts thereof with mineral or organic acids and solvates and/or hydrates thereof, characterized in that: a compound of formula:

in which R₁, R₂, R₃, R₄, R₅ and R₆ are as defined for a compound of formula (I) in claim 1, is reacted, in the presence of a base, with a halide of formula:

in which R₇ and R₈ are as defined for a compound of formula (I) in claim 1 and Hal represents a halogen atom.
 8. Compound of formula:

in which: R₁ represents a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; a trifluoromethyl radical; a trifluoromethoxy radical; R₂ represents a hydrogen atom; a halogen atom; a (C₁-C₄)alkyl; a (C₁-C₄)alkoxy; a trifluoromethyl radical; or R₂ is in position -6- of the indol-2-one ring and R₁ and R₂ together represent a divalent trimethylene radical; R₃ represents a halogen atom; a hydroxyl; a (C₁-C₄)alkyl; a (C₁-C₂)alkoxy; a trifluoromethoxy radical; R₄ represents a hydrogen atom; a halogen atom; a (C₁-C₂)alkyl; a (C₁-C₂)alkoxy; or R₄ is in position -3- of the phenyl and R₃ and R₄ together represent a methylenedioxy radical; R₅ represents an ethylamino group; a dimethylamino group; an azetidin-1-yl radical; a (C₁-C₂)alkoxy; R₆ represents a hydrogen atom; a (C₁-C₄)alkyl; a group —(CH₂)n-CO—R₉; a group —CO— (CH₂)n-NR₁₀R₁₁; R₉ represents a hydroxyl; a (C₁-C₄)alkoxy; a group —NR₁₂R₁₃; R₁₀ and R₁₁ each independently represent a (C₁-C₄) alkyl; or R₁₀ and R₁₁, together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl; R₁₂ represents a hydrogen or a (C₁-C₄)alkyl; R₁₃ represents a (C₁-C₄)alkyl; a —C(CH₃)₂CH₂OH group; a —C(CH₃)(CH₂OH)₂ group; a —C(CH₂OH)₃ group; or R₁₂ and R₁₃, together with the nitrogen atom to which they are attached, constitute a heterocyclic radical chosen from: azetidin-1-yl, pyrrolidin-1-yl, piperid-1-yl, piperazin-1-yl, morpholin-4-yl or thiomorpholin-4-yl; n is 1 or 2; and the salts thereof with mineral or organic acids, in the form of an optically pure isomer or in the form of a mixture of diastereoisomers.
 9. Pharmaceutical composition comprising, as active principle, a compound according to any one of claims 1 to 6, pharmaceutically acceptable salts thereof with mineral or organic acids, and pharmaceutically acceptable solvates and/or hydrates thereof.
 10. Use of a compound according to any one of claims 1 to 6, pharmaceutically acceptable salts thereof with mineral or organic acids, and pharmaceutically acceptable solvates and/or hydrates thereof, for the preparation of medicinal products intended for treating any pathology in which arginine-vasopressin and/or its V_(1b) receptors or both its V_(1b) receptors and its V_(1a) receptors are involved.
 11. Medicinal product characterized in that it consists of a compound according to any one of claims 1 to
 6. 